Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A002
D. Araujo, S. D’Angelo, G. Demetri, M. Druta, J. Glod, W. Chow, W. Tap, J. Senra, R. Abbott, E. V. Winkle, K. Chagin, M. Maroto, E. Norry, M. Iyengar, T. Trivedi, A. Gerry, R. Amado, C. Mackall
Background: NY-ESO-1c259 is an affinity optimized TCR recognizing an NY-ESO-1-derived peptide complexed with HLA-A*02 (SPEAR T-cells). NY-ESO-1c259TCR therapy induced responses in ~50% of patients whose tumors express high level NY-ESO-1 (NCT01343043). Here we report on preclinical studies of TCR activity and results from a cohort of patients whose tumors express low NY-ESO-1 levels. Methods: T-cell response against tumor-derived cell lines with differential NY-ESO-1 expression levels was assessed by ELISA. Patients had selected HLA subtypes (HLA-A*02:01, 02:05, 02:06) and advanced NY-ESO-1+ SS. In this cohort, tumors express NY-ESO-1 at ≥ 1+ in > 1% but 1×10e4 mRNA copies/10e6 reference gene transcripts. Ten patients in this cohort have been treated (as of 23Nov17). One died due to disease progression 2 days post infusion. Four have had a partial response (ORR 40%), and median duration of response was 8.5 weeks (range, 8-13). Antigen expression level by IHC (% 1+, 2+, and/or 3+), best overall response (BOR) by RECIST v1.1, and transduced cell expansion (copies/microgram DNA) are listed below for the 9 evaluable patients: Pt 264, 30% 1+/2+, PR, 86320; Pt 313, 90% 1+, PR, 45430; Pt 325, 10% 2+, PR, 13365; Pt 331, 40% 1+, 10% 2+, 10% 3+, PR, 197546; Pt 324, 50% 1+, 10% 2+, SD, 133334; Pt 305, 5% 1+, 5% 2+, 5% 3+, SD, 74855; Pt 322, 50% 1+, 10% 2+, SD, 54569; Pt 323, 20% 1+, 10% 2+, SD, 50912; Pt 211, 10% 1+, 20% 2+, 20% 3+, PD, 22627. Conclusions: In vitro assays can assess mRNA levels and protein expression of target antigen required for T-cell activation and cytotoxicity, predicting expression levels required for anti-tumor activity in vivo. The patient data suggest that affinity optimized TCRs can be used to treat tumors with low target antigen expression. Citation Format: Dejka Araujo, Sandra D9Angelo, George Demetri, Mihaela Druta, John Glod, Warren Chow, William Tap, Joana Senra, Rachel Abbott, Erin Van Winkle, Karen Chagin, Miguel Maroto, Elliot Norry, Malini Iyengar, Trupti Trivedi, Andrew Gerry, Rafael Amado, Crystal Mackall. Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A002.
{"title":"Abstract A002: Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen","authors":"D. Araujo, S. D’Angelo, G. Demetri, M. Druta, J. Glod, W. Chow, W. Tap, J. Senra, R. Abbott, E. V. Winkle, K. Chagin, M. Maroto, E. Norry, M. Iyengar, T. Trivedi, A. Gerry, R. Amado, C. Mackall","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A002","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A002","url":null,"abstract":"Background: NY-ESO-1c259 is an affinity optimized TCR recognizing an NY-ESO-1-derived peptide complexed with HLA-A*02 (SPEAR T-cells). NY-ESO-1c259TCR therapy induced responses in ~50% of patients whose tumors express high level NY-ESO-1 (NCT01343043). Here we report on preclinical studies of TCR activity and results from a cohort of patients whose tumors express low NY-ESO-1 levels. Methods: T-cell response against tumor-derived cell lines with differential NY-ESO-1 expression levels was assessed by ELISA. Patients had selected HLA subtypes (HLA-A*02:01, 02:05, 02:06) and advanced NY-ESO-1+ SS. In this cohort, tumors express NY-ESO-1 at ≥ 1+ in > 1% but 1×10e4 mRNA copies/10e6 reference gene transcripts. Ten patients in this cohort have been treated (as of 23Nov17). One died due to disease progression 2 days post infusion. Four have had a partial response (ORR 40%), and median duration of response was 8.5 weeks (range, 8-13). Antigen expression level by IHC (% 1+, 2+, and/or 3+), best overall response (BOR) by RECIST v1.1, and transduced cell expansion (copies/microgram DNA) are listed below for the 9 evaluable patients: Pt 264, 30% 1+/2+, PR, 86320; Pt 313, 90% 1+, PR, 45430; Pt 325, 10% 2+, PR, 13365; Pt 331, 40% 1+, 10% 2+, 10% 3+, PR, 197546; Pt 324, 50% 1+, 10% 2+, SD, 133334; Pt 305, 5% 1+, 5% 2+, 5% 3+, SD, 74855; Pt 322, 50% 1+, 10% 2+, SD, 54569; Pt 323, 20% 1+, 10% 2+, SD, 50912; Pt 211, 10% 1+, 20% 2+, 20% 3+, PD, 22627. Conclusions: In vitro assays can assess mRNA levels and protein expression of target antigen required for T-cell activation and cytotoxicity, predicting expression levels required for anti-tumor activity in vivo. The patient data suggest that affinity optimized TCRs can be used to treat tumors with low target antigen expression. Citation Format: Dejka Araujo, Sandra D9Angelo, George Demetri, Mihaela Druta, John Glod, Warren Chow, William Tap, Joana Senra, Rachel Abbott, Erin Van Winkle, Karen Chagin, Miguel Maroto, Elliot Norry, Malini Iyengar, Trupti Trivedi, Andrew Gerry, Rafael Amado, Crystal Mackall. Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A002.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126003147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A012
M. Lacher, Sanne Graeve, V. Sunkari, D. Adams, Cha-Mei Tang, P. Amstutz, C. Wiseman, G. Peoples, W. Williams
Background: SV-BR-1-GM is a GM-CSF-engineered breast cancer cell line employed – after irradiation – as a targeted immunotherapy for advanced breast cancer. Tumor regressions at metastatic sites have been observed, most notably in patients with HLA allele matches to the cell line. We are assessing SV-BR-1-GM in the phase IIa portion of a phase I/IIa clinical trial in metastatic and locally recurrent breast cancer (ClinicalTrials.gov identifier NCT03066947). Additionally, we are co-developing a companion diagnostic (BriaDX™) to identify patients likely to respond to SV-BR-1-GM. Currently, BriaDX™ consists of HLA typing; however, we have begun assessing biomarkers in sera, lymphocyte characteristics, circulating tumor cells (CTCs), and cancer-associated macrophage-like cells (CAMLs) from patients collected at baseline and after inoculation of SV-BR-1-GM to layer in additional components to improve accuracy, with the number/subtyping of CTCs and CAMLs being prognostic indicators. Methods: Subjects are pretreated with low-dose cyclophosphamide to reduce immune suppression. SV-BR-1-GM is inoculated intradermally with follow-up local injections of IFNα2. Cycles are every 2 weeks x 3, then monthly. HLA typing was conducted via LabType R-SSO Kits (One Lambda). Cytokines were measured via single- or multiplex assays. Anti-SV-BR-1 antibodies were determined by incubation of SV-BR-1 cells with diluted patient sera followed by staining with a fluorescently-labeled anti-IgG antibody and detection by flow cytometry. CTCs and CAMLs were evaluated by CellSieve™ at Creatv MicroTech. Results: To date, 16 clinical trial subjects have been inoculated with the SV-BR-1-GM regimen as rescue immunotherapy. All were treatment refractory and had received a median of 4.5 prior chemo/biologic therapy regimens (range 1-13). Two of the 16 patients remained on study for ≥3 months (5 cycles) with 4 patients currently on study not having reached the 3-month evaluation time point. Objective regression of tumor was seen in 2 subjects. One subject had virtually complete regression of 20 of 20 lung metastases noted at 3 and 6 months (but with progressive bone and liver metastases). Another subject had improvement of chest wall metastases and quality of life but expired due to nontreatment-related causes. Response appeared to correlate with HLA allele-matching to SV-BR-1-GM. Anti-SV-BR-1 antibody titers increased in several patients. Among the cytokines assessed, interleukin (IL)-8 levels increased in HLA-DRB3 allele-matched subjects after SV-BR-1-GM inoculation. Of 15 patients evaluated, CTCs were present in 6 patients at baseline while CAMLs were present in all 15. Five of 5 patients evaluated for PD-L1 expression had mostly low-to-medium expression of PD-L1 on their CTCs/CAMLs. In the patient who had regression of lung metastases but progression of liver metastases, PD-L1 expression and maximum CAML size increased, but the number of CAMLs decreased during treatment. CAML number al
背景:SV-BR-1-GM是一种gm - csf工程的乳腺癌细胞系，经照射后可作为晚期乳腺癌的靶向免疫治疗。已经观察到转移部位的肿瘤消退，最明显的是HLA等位基因与细胞系匹配的患者。我们正在转移性和局部复发性乳腺癌(ClinicalTrials.gov标识符NCT03066947)的I/IIa期临床试验中评估SV-BR-1-GM。此外，我们正在共同开发一种伴随诊断(BriaDX™)，以识别可能对SV-BR-1-GM有反应的患者。目前，BriaDX™包括HLA分型;然而，我们已经开始评估基线和接种SV-BR-1-GM后收集的患者血清、淋巴细胞特征、循环肿瘤细胞(CTCs)和癌症相关巨噬细胞样细胞(caml)中的生物标志物，以添加其他成分以提高准确性，CTCs和caml的数量/亚型作为预后指标。方法:采用低剂量环磷酰胺预处理，减轻免疫抑制。SV-BR-1-GM皮下接种，随后局部注射IFNα2。周期是每2周× 3次，然后是每月一次。HLA分型采用LabType R-SSO试剂盒(One Lambda)。细胞因子通过单一或多重测定来测定。通过将SV-BR-1细胞与稀释的患者血清孵育，然后用荧光标记的抗igg抗体染色，流式细胞术检测抗SV-BR-1抗体。CTCs和caml采用Creatv MicroTech公司的CellSieve™进行评估。结果:迄今为止，已有16名临床试验受试者接种了SV-BR-1-GM方案作为救援免疫治疗。所有患者均为难治性患者，既往化疗/生物治疗方案中位数为4.5次(范围1-13次)。16例患者中有2例仍在研究中≥3个月(5个周期)，目前有4例患者在研究中尚未达到3个月的评估时间点。目的:2例患者肿瘤消退。一名受试者在3个月和6个月时发现20个肺转移灶中的20个几乎完全消退(但伴有进行性骨和肝转移)。另一名患者的胸壁转移和生活质量有所改善，但由于与治疗无关的原因而死亡。应答似乎与SV-BR-1-GM的HLA等位基因匹配有关。一些患者的抗sv - br -1抗体滴度升高。在所评估的细胞因子中，接种SV-BR-1-GM后，HLA-DRB3等位基因匹配的受试者中白细胞介素(IL)-8水平升高。在评估的15例患者中，基线时6例患者存在ctc，而所有15例患者均存在caml。5例评估PD-L1表达的患者中有5例在其ctc / caml上的PD-L1表达大多为低至中水平。在肺转移消退而肝转移进展的患者中，治疗期间PD-L1表达和最大CAML大小增加，但CAML数量减少。在一名达到3个月评估访问且无进展的患者和一名因炎症恶化而退出的炎性乳腺癌患者中，CAML数量也有所减少。结论:除了患者的HLA类型外，一些药效学参数与肿瘤消退和/或HLA匹配状态相关。ctc或caml在该人群中经常检测到，PD-L1表达在这些细胞中很常见。CAML的数量和大小似乎都与反应有关，尽管还需要更大规模的研究。未来的步骤包括评估SV-BR-1-GM与检查点抑制剂。引用格式:Markus D. Lacher, Sanne Graeve, Vivekananda (Vivek) Sunkari, Daniel L. Adams, Cha-Mei Tang, Pete Amstutz, Charles L. Wiseman, George E. Peoples, William V. Williams晚期乳腺癌全细胞靶向免疫疗法SV-BR-1-GM:反应的药效学标志物[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A012。
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Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A005
A. Blázquez, A. Rubinsteyn, Julia Kodysh, J. Finnigan, T. Marron, R. Sabado, M. Meseck, Tim O’Donnell, Jeff Hammerbacher, M. Donovan, J. Holt, M. Mahajan, J. Mandeli, K. Misiukiewicz, E. Genden, Brett A. Milles, H. Khorasani, P. Dottino, H. Irie, A. Tiersten, E. Port, A. Wolf, He-Jin Cho, A. Tewari, S. Parekh, S. Nair, M. Galsky, W. Oh, S. Gnjatic, E. Schadt, P. Friedlander, N. Bhardwaj
Introduction: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations, including nucleotide substitutions, insertions, and deletions that occur during carcinogenesis. These somatic variations can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematologic malignanicies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens. The single-center study will enroll 20 eligible subjects with histologic diagnosis of solid and hematologic malignancies. Subjects must have no measurable disease at time of first vaccine administration, and 5-year disease recurrence risk of > 30%. Toxicity will be defined by CTCAE v5.0. Blood samples will be collected at various time points for immune response monitoring. Each patient’s vaccine peptides are selected by identifying somatic mutations from comparison of tumor and normal exome sequencing data, phasing somatic variants with co-occurring germline variants using tumor RNA sequencing data, and ranking mutated peptide sequences ”Openvax pipeline.” The process for determining somatic variants hews closely to the Broad Institute’s “Best Practices” for cancer SNVs and indels. The phasing of somatic and germline variants is implemented in a custom bioinformatics tool called Isovar. Mutated protein sequences containing phased variants are ranked according to two criteria: expression of the mutant allele in tumor RNA and aggregated predicted affinity to the patient’s Class I MHCs. Both quantities are normalized and multiplied together to create single ranked ordering of the candidate mutant sequences. Results: PGV001_002 (head and neck squamous cell cancer), who has completed vaccination, received 10 doses of vaccine comprising 10 long peptides (25 amino acid length) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced blood T-cell responses were determined, at weeks 0 (before-treatment) and 27 (after-treatment), ex vivo by interferon (IFN)-g enzyme-linked immunospot (ELISPOT) assay and after in vitro expansion by intracellular cytokine staining (ICS). Overlapping 15-16-mer assays peptides (OLPs) spanning the entirety of each ILP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled and used to monitor immunogenicity. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4+ and CD8+ T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-α, TNF-α, and/or IL-2) from either CD4+ or CD8+ T-cells. C
简介:突变衍生肿瘤抗原(mta)是体细胞变异的直接结果，包括在癌变过程中发生的核苷酸替换、插入和缺失。这些体细胞变异可以通过基因测序来表征，并用于鉴定mta。我们为基于mta的完全个性化疫苗开发了一个平台，用于辅助治疗实体和血液恶性肿瘤。方法:这是一项单臂、开放标签、概念验证的I期研究，旨在测试个性化基因组疫苗001 (PGV001)的安全性和免疫原性，该疫苗可靶向多达10种预测的个人肿瘤新抗原。该单中心研究将招募20名组织学诊断为实体和血液恶性肿瘤的合格受试者。受试者在第一次接种疫苗时必须没有可测量的疾病，5年疾病复发风险为30%。毒性将由CTCAE v5.0定义。在不同的时间点采集血液样本进行免疫反应监测。通过比较肿瘤和正常外显子组测序数据来确定体细胞突变，利用肿瘤RNA测序数据将体细胞变异与共同发生的种系变异分阶段，并将突变肽序列排列在“Openvax管道”中，从而选择每个患者的疫苗肽。确定体细胞变异的过程与Broad研究所针对癌症snv和indel的“最佳实践”密切相关。体细胞和种系变异的分期是在一个名为Isovar的定制生物信息学工具中实现的。包含阶段性变异的突变蛋白序列根据两个标准进行排序:突变等位基因在肿瘤RNA中的表达以及与患者I类MHCs的聚合预测亲和力。这两个量被归一化并相乘，以创建候选突变序列的单一排序。结果:完成疫苗接种的PGV001_002(头颈部鳞状细胞癌)接受了10剂由10个长肽(25个氨基酸长度)联合poly-ICLC (toll样受体-3激动剂)组成的皮内疫苗。在第0周(治疗前)和第27周(治疗后)，通过体外干扰素(IFN)-g酶联免疫斑点(ELISPOT)测定和细胞内细胞因子染色(ICS)体外扩增后测定疫苗诱导的血液t细胞应答。重叠的15-16-mer测试肽(OLPs)跨越每个ILP的整个和9-10-mer肽对应于每个预测的I类表位(Min)被合并并用于监测免疫原性。对这些肽库的体外反应在第0周无法检测到，但在第27周对10个OLPs中的2个(20%)和5 Min中的10个(50%)有明显的反应。体外扩增后，10个聚合肽中有5个(50%)出现新抗原特异性CD4+和CD8+ t细胞反应。10个表位中有7个(70%)引起CD4+或CD8+ t细胞的多功能t细胞反应(分泌INF-α， TNF-α和/或IL-2)。结论:为了确定肽库中哪些预测表位刺激了t细胞反应，我们通过离体和体外扩增对所有肽库进行了反卷积。体外检测到15个(15-mer)肽中有1个(6.7%)产生IFN-α， 22个(9-10-mer)肽中有4个(18.2%)产生IFN-α。用单肽扩增后，在22个(9-10-mer)肽中，CD8+ t细胞对13个(59%)肽有反应，而对15个(15-16-mer)肽中的11个有CD4+反应。CD4+和CD8+ t细胞反应都是多功能的。在我们的第一位患者中，PGV001疫苗显示出安全性和免疫原性，引起对疫苗肽的CD4+和CD8+反应。由于我们正在招募更多的患者，从这项临床试验中获得的信息将指导下一代基于mta的疫苗、免疫治疗方法的未来发展和合理的组合。引文格式:Ana B. Blazquez, Alex rubinsten, Julia kodih, John P. Finnigan, Thomas Marron, Rachel L. Sabado, Marcia Meseck, Timothy J. O9Donnell, Jeffrey Hammerbacher, Michael Donovan, John Holt, Milind Mahajan, John Mandeli, Krysztof Misiukiewicz, Eric M. Genden, Brett A. Milles, Hooman Khorasani, Peter R. Dottino, Hanna Irie, Amy B. Tiersten, Elisa R. Port, Andrea S. Wolf, Hern J. Cho, Ashutosh Tewari, Samir S. Parekh, Sujit Nair, Matthew D. Galsky, William K. Oh, Sacha Gnjatic, Eric E. Schadt，Phillip A. Friedlander, Nina Bhardwaj。一种多肽个性化基因组疫苗辅助治疗实体癌的安全性和免疫原性的I期研究[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志，2019;7(2增刊):摘要nr A005。
{"title":"Abstract A005: A phase I study of the safety and immunogenicity of a multipeptide personalized genomic vaccine in the adjuvant treatment of solid cancers","authors":"A. Blázquez, A. Rubinsteyn, Julia Kodysh, J. Finnigan, T. Marron, R. Sabado, M. Meseck, Tim O’Donnell, Jeff Hammerbacher, M. Donovan, J. Holt, M. Mahajan, J. Mandeli, K. Misiukiewicz, E. Genden, Brett A. Milles, H. Khorasani, P. Dottino, H. Irie, A. Tiersten, E. Port, A. Wolf, He-Jin Cho, A. Tewari, S. Parekh, S. Nair, M. Galsky, W. Oh, S. Gnjatic, E. Schadt, P. Friedlander, N. Bhardwaj","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A005","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A005","url":null,"abstract":"Introduction: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations, including nucleotide substitutions, insertions, and deletions that occur during carcinogenesis. These somatic variations can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematologic malignanicies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens. The single-center study will enroll 20 eligible subjects with histologic diagnosis of solid and hematologic malignancies. Subjects must have no measurable disease at time of first vaccine administration, and 5-year disease recurrence risk of > 30%. Toxicity will be defined by CTCAE v5.0. Blood samples will be collected at various time points for immune response monitoring. Each patient’s vaccine peptides are selected by identifying somatic mutations from comparison of tumor and normal exome sequencing data, phasing somatic variants with co-occurring germline variants using tumor RNA sequencing data, and ranking mutated peptide sequences ”Openvax pipeline.” The process for determining somatic variants hews closely to the Broad Institute’s “Best Practices” for cancer SNVs and indels. The phasing of somatic and germline variants is implemented in a custom bioinformatics tool called Isovar. Mutated protein sequences containing phased variants are ranked according to two criteria: expression of the mutant allele in tumor RNA and aggregated predicted affinity to the patient’s Class I MHCs. Both quantities are normalized and multiplied together to create single ranked ordering of the candidate mutant sequences. Results: PGV001_002 (head and neck squamous cell cancer), who has completed vaccination, received 10 doses of vaccine comprising 10 long peptides (25 amino acid length) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced blood T-cell responses were determined, at weeks 0 (before-treatment) and 27 (after-treatment), ex vivo by interferon (IFN)-g enzyme-linked immunospot (ELISPOT) assay and after in vitro expansion by intracellular cytokine staining (ICS). Overlapping 15-16-mer assays peptides (OLPs) spanning the entirety of each ILP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled and used to monitor immunogenicity. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4+ and CD8+ T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-α, TNF-α, and/or IL-2) from either CD4+ or CD8+ T-cells. C","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"253 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132601229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A014
Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiangle Sun, Lin Yang
Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation. Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.
{"title":"Abstract A014: Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy","authors":"Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiangle Sun, Lin Yang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A014","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A014","url":null,"abstract":"Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation. Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126067303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A011
F. Janku, M. Gounder, A. Pezeshki, R. Murthy, A. Wang-Gillam, D. Shepard, D. Hong, S. Piha-Paul, Anjali Raina, A. Leontovich, G. Decrescenzo, B. Kreider, David Tung, M. Varterasian, H. Zhang, K. Khazaie
Bacteriolytic strategies offer unique advantages to combat a broad range of cancers often refractive to conventional chemotherapies and/or radiotherapies. C. novyi-NT is an attenuated strain of Clostridium novyi, a spore-forming, gram-positive, obligate anaerobe that lacks a lethal alpha- toxin, expressed by the parental strain. When administered intravenously or intratumorally with percutaneous injection, C. novyi-NT colonizes and replicates within the hypoxic region of the tumors, eliciting robust, tumor-confined cell lysis. In this first-in-man phase 1 study, patients with injectable treatment-refractory solid tumors received a single intratumoral injection of C. novyi-NT spores across 6 dose cohorts (spore concentrations of 104, 3x104, 105, 3x105, 106, 3x106) using a 3+3 trial design. The primary endpoints were to assess the safety profile, the dose limiting toxicity, and the maximum tolerated dose of C. novyi-NT. Key secondary endpoints included assessments of the preliminary antitumor activity of the injected tumor, an overall response evaluated by RECIST v. 1.1, and the host immune and inflammatory response to C. novyi-NT. Twenty-four patients were enrolled between November, 2013 and April, 2017. A single intratumoral injection of C. novyi-NT led to germination and resultant tumor lysis of injected tumor masses in 46% of patients across all dosing cohorts. The cohort 5 dose of 106 spores was defined as the maximum tolerated dose. Dose-limiting toxicities were grade 4 sepsis and grade 4 gas gangrene (n=1), all in patients with germination. In the 22 evaluable patients, 21 (95%) had stable disease (SD) as the best response for the injected lesion (tumor shrinkage of > 10% was observed in 21% of patients) and 19 (86%) had overall SD as the best response per RECIST 1.1. C. novyi-NT injection resulted in transient serum cytokine responses consistent with inflammasome activity, activation of innate immunity, tissue remodeling, and angiogenesis. Tumor antigen specific ELISPOT assays pre- and post- treatment documented enhanced secretion of IFNγ and TNFα by circulating T-cells, indicating improved systemic tumor specific T-cell responses. Multiparametric in situ immunostaining of core biopsies suggested improved immune cell infiltration in metastatic lesions. These early signs of improved antitumor activity in patients with advanced solid tumors have encouraged a new trial of C. novyi-NT in combination with immune checkpoint inhibitors. Citation Format: Filip Janku, Mrinal Gounder, Abdul Mohammad Pezeshki, Ravi Murthy, Andrea Wang-Gillam, Dale Shepard, David S. Hong, Sarina A. Piha-Paul, Anjali Raina, Alexey A. Leontovich, Gary DeCrescenzo, Brent L. Kreider, David Tung, Mary Varterasian, Halle H. Zhang, Khashayarsha Khazaie. First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses [abstract]. In: Proceedings of the Fourth
溶菌策略提供了独特的优势，以对抗广泛的癌症，通常是传统化疗和/或放疗的屈光度。新梭菌nt是新梭菌的减毒菌株，是一种芽孢形成的革兰氏阳性专性厌氧菌，缺乏致命的α -毒素，由亲本菌株表达。当静脉注射或经皮注射肿瘤内时，C. novyi-NT在肿瘤的缺氧区定植和复制，引发强大的肿瘤局限性细胞溶解。在这项首次在人体内进行的1期研究中，采用3+3试验设计，可注射治疗难治性实体瘤患者接受了6个剂量队列(孢子浓度为104、3x104、105、3x105、106、3x106)的单次瘤内注射C. novyi-NT孢子。主要终点是评估C. novyi-NT的安全性、剂量限制性毒性和最大耐受剂量。关键次要终点包括注射肿瘤的初步抗肿瘤活性评估，RECIST v. 1.1评估的总体反应，以及宿主对C. novyi-NT的免疫和炎症反应。24名患者于2013年11月至2017年4月入组。在所有给药队列中，46%的患者单次肿瘤内注射C. novyi-NT导致肿瘤萌发并导致肿瘤溶解。队列5的106个孢子剂量被定义为最大耐受剂量。剂量限制性毒性为4级败血症和4级气性坏疽(n=1)，均发生在萌发患者中。在22例可评估的患者中，21例(95%)的疾病稳定(SD)是注射病变的最佳缓解(21%的患者观察到肿瘤缩小> 10%)，19例(86%)的总体SD是RECIST 1.1的最佳缓解。注射C. novyi-NT导致短暂的血清细胞因子反应，与炎性小体活性、先天免疫激活、组织重塑和血管生成一致。肿瘤抗原特异性ELISPOT检测显示，治疗前后循环t细胞分泌IFNγ和TNFα增强，表明全身肿瘤特异性t细胞反应改善。核心活检的多参数原位免疫染色提示转移性病变中免疫细胞浸润改善。这些早期迹象表明晚期实体瘤患者的抗肿瘤活性有所改善，这鼓励了C. novyi-NT联合免疫检查点抑制剂的新试验。引文格式:philip Janku, Mrinal Gounder, Abdul Mohammad Pezeshki, Ravi Murthy, Andrea Wang-Gillam, Dale Shepard, David S. Hong, Sarina A. Piha-Paul, Anjali Raina, Alexey A. Leontovich, Gary DeCrescenzo, Brent L. Kreider, David Tung, Mary Varterasian, Halle H. Zhang, Khashayarsha Khazaie。难治性晚期实体瘤患者瘤内注射Clostridiumnovyi-NT孢子的首次人体临床试验:安全性、活性和免疫反应[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A011。
{"title":"Abstract A011: First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses","authors":"F. Janku, M. Gounder, A. Pezeshki, R. Murthy, A. Wang-Gillam, D. Shepard, D. Hong, S. Piha-Paul, Anjali Raina, A. Leontovich, G. Decrescenzo, B. Kreider, David Tung, M. Varterasian, H. Zhang, K. Khazaie","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A011","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A011","url":null,"abstract":"Bacteriolytic strategies offer unique advantages to combat a broad range of cancers often refractive to conventional chemotherapies and/or radiotherapies. C. novyi-NT is an attenuated strain of Clostridium novyi, a spore-forming, gram-positive, obligate anaerobe that lacks a lethal alpha- toxin, expressed by the parental strain. When administered intravenously or intratumorally with percutaneous injection, C. novyi-NT colonizes and replicates within the hypoxic region of the tumors, eliciting robust, tumor-confined cell lysis. In this first-in-man phase 1 study, patients with injectable treatment-refractory solid tumors received a single intratumoral injection of C. novyi-NT spores across 6 dose cohorts (spore concentrations of 104, 3x104, 105, 3x105, 106, 3x106) using a 3+3 trial design. The primary endpoints were to assess the safety profile, the dose limiting toxicity, and the maximum tolerated dose of C. novyi-NT. Key secondary endpoints included assessments of the preliminary antitumor activity of the injected tumor, an overall response evaluated by RECIST v. 1.1, and the host immune and inflammatory response to C. novyi-NT. Twenty-four patients were enrolled between November, 2013 and April, 2017. A single intratumoral injection of C. novyi-NT led to germination and resultant tumor lysis of injected tumor masses in 46% of patients across all dosing cohorts. The cohort 5 dose of 106 spores was defined as the maximum tolerated dose. Dose-limiting toxicities were grade 4 sepsis and grade 4 gas gangrene (n=1), all in patients with germination. In the 22 evaluable patients, 21 (95%) had stable disease (SD) as the best response for the injected lesion (tumor shrinkage of > 10% was observed in 21% of patients) and 19 (86%) had overall SD as the best response per RECIST 1.1. C. novyi-NT injection resulted in transient serum cytokine responses consistent with inflammasome activity, activation of innate immunity, tissue remodeling, and angiogenesis. Tumor antigen specific ELISPOT assays pre- and post- treatment documented enhanced secretion of IFNγ and TNFα by circulating T-cells, indicating improved systemic tumor specific T-cell responses. Multiparametric in situ immunostaining of core biopsies suggested improved immune cell infiltration in metastatic lesions. These early signs of improved antitumor activity in patients with advanced solid tumors have encouraged a new trial of C. novyi-NT in combination with immune checkpoint inhibitors. Citation Format: Filip Janku, Mrinal Gounder, Abdul Mohammad Pezeshki, Ravi Murthy, Andrea Wang-Gillam, Dale Shepard, David S. Hong, Sarina A. Piha-Paul, Anjali Raina, Alexey A. Leontovich, Gary DeCrescenzo, Brent L. Kreider, David Tung, Mary Varterasian, Halle H. Zhang, Khashayarsha Khazaie. First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses [abstract]. In: Proceedings of the Fourth ","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127023887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A008
Shilpa Gupta, C. Weight, N. Agarwal, Sumati V Gupta, B. Konety, E. Gibb, E. Davicioni, B. Thyagarajan, G. Sonpavde
Background: Cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). Immunotherapy with checkpoint inhibitors has improved outcomes in advanced bladder cancer and immunotherapy is synergistic with chemotherapy. Our ongoing trial is aimed at studying the efficacy and safety of nivolumab (N)with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC (NCT03294304). Methods: This is a single-arm, multicenter phase II study for patients with MIBC eligible for neoadjuvant GC and planned for RC. Forty-one patients will be treated with N+ GC every 21 days for 4 treatment cycles over 12 weeks followed by RC. The primary endpoint is PaR. Key inclusion criteria are presence of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring Citation Format: Shilpa Gupta, Christopher J. Weight, Neeraj Agarwal, Sumati Gupta, Badrinath Konety, Ewan Gibb, Elai Davicioni, Bharat Thyagarajan, Guru Sonpavde. Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A008.
背景:以顺铂为基础的新辅助化疗可提高肌肉浸润性膀胱癌(MIBC)的生存率，这与根治性膀胱切除术(RC)的病理反应(PaR)相关。免疫治疗检查点抑制剂改善了晚期膀胱癌的预后，免疫治疗与化疗具有协同作用。我们正在进行的试验旨在研究nivolumab (N)联合吉西他滨-顺铂(GC)作为新辅助治疗MIBC (NCT03294304)的有效性和安全性。方法:这是一项单臂、多中心II期研究，研究对象是符合新辅助GC治疗条件并计划进行RC治疗的MIBC患者。41例患者将每21天接受N+ GC治疗，共4个治疗周期，为期12周，然后进行RC治疗。主要终点是PaR。主要纳入标准是临床分期为T2-T4a和N≤1疾病(孤立淋巴结测量)的MIBC(主要是尿路上皮癌)的存在。引文格式:Shilpa Gupta, Christopher J. Weight, Neeraj Agarwal, Sumati Gupta, Badrinath Konety, Ewan Gibb, Elai Davicioni, Bharat Thyagarajan, Guru Sonpavde。新辅助纳武单抗、吉西他滨和顺铂治疗肌肉浸润性膀胱癌:研究进展[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫，2019;7(2增刊):摘要nr A008。
{"title":"Abstract A008: Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update","authors":"Shilpa Gupta, C. Weight, N. Agarwal, Sumati V Gupta, B. Konety, E. Gibb, E. Davicioni, B. Thyagarajan, G. Sonpavde","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A008","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A008","url":null,"abstract":"Background: Cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). Immunotherapy with checkpoint inhibitors has improved outcomes in advanced bladder cancer and immunotherapy is synergistic with chemotherapy. Our ongoing trial is aimed at studying the efficacy and safety of nivolumab (N)with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC (NCT03294304). Methods: This is a single-arm, multicenter phase II study for patients with MIBC eligible for neoadjuvant GC and planned for RC. Forty-one patients will be treated with N+ GC every 21 days for 4 treatment cycles over 12 weeks followed by RC. The primary endpoint is PaR. Key inclusion criteria are presence of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring Citation Format: Shilpa Gupta, Christopher J. Weight, Neeraj Agarwal, Sumati Gupta, Badrinath Konety, Ewan Gibb, Elai Davicioni, Bharat Thyagarajan, Guru Sonpavde. Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A008.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122645586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A007
S. D’Angelo, D. Araujo, B. A. Tine, G. Demetri, M. Dutra, J. Glod, W. Chow, S. Grupp, Alibiruni Abdul Razak, W. Tap, B. Wilky, E. V. Winkle, E. Norry, Samik Basu, K. Chagin, M. Iyengar, T. Trivedi, R. Amado, C. Mackall
Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials. Citation Format: Sandra P. D9Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival
背景:ny - eso - 1c259t细胞识别NY-ESO-1衍生肽与HLA-A*02复合物(SPEAR t细胞)正在滑膜肉瘤(NCT01343043)的多队列临床试验中进行研究。我们比较了使用不同剂量淋巴细胞消耗化疗的两个队列的安全性、有效性和细胞持久性。方法:根据不同的抗原表达水平和淋巴细胞去除方案分为四个队列，该评估比较了队列1(关闭)和队列4(正在进行)。在这两组患者中，免疫组化结果显示，≥50%的患者肿瘤细胞以2+/3+水平表达NY-ESO-1。分离后，t细胞被分离、激活、转导以表达NY-ESO-1c259T并扩增。队列1淋巴细胞耗用氟达拉滨30 mg/m2/d × 4 d，环磷酰胺1800 mg/m2/d × 2d，队列4氟达拉滨30 mg/m2/d × 3d，环磷酰胺600 mg/m2/d × 3d。靶剂量为1-6 × 109个转导细胞。在第4、8和12周以及每3个月评估一次疾病，直到疾病进展。结果:队列1治疗12例，队列4治疗14例(截至2017年11月23日)。队列1的中位转导细胞剂量为3.6 × 109个细胞，队列4为2.6 × 109个细胞。治疗相关不良事件(ae)在队列1中为100%，在队列4中为86%;50%的队列1和14%的队列4报告了相关的严重不良事件(sae)。没有致命的ae。队列4的总缓解率(ORR)为29%，而队列1为50%，队列4的缓解持续时间为16周，而队列1为31周。稳定的最佳总体反应在队列1中为50%，在队列4中为64%。应答者外周血中转导t细胞扩增的中位峰值在队列4(40,137拷贝/μg DNA)低于队列1(106,174拷贝/μg DNA)。队列1的绝对淋巴细胞计数中位数为1×107/L(范围0-3)，队列4的绝对淋巴细胞计数中位数为9×107/L(范围0-40)。结论:队列1中更高的ORR和更高的峰值扩张可能归因于淋巴细胞消耗方案的剂量强度。尽管在队列1中相关的sae报告比例高于队列4，但两者的安全性和耐受性都是可接受的，细胞剂量相似。数据和总体收益:风险考虑支持在未来试验中使用更高剂量的预处理化疗。引文格式:Sandra P. D9Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall。基因工程ny - eso - 1c259t细胞治疗滑膜肉瘤患者的两组前期研究中预处理对疗效的影响比较[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志，2019;7(2增刊):摘要nr A007。
{"title":"Abstract A007: Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma","authors":"S. D’Angelo, D. Araujo, B. A. Tine, G. Demetri, M. Dutra, J. Glod, W. Chow, S. Grupp, Alibiruni Abdul Razak, W. Tap, B. Wilky, E. V. Winkle, E. Norry, Samik Basu, K. Chagin, M. Iyengar, T. Trivedi, R. Amado, C. Mackall","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A007","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A007","url":null,"abstract":"Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials. Citation Format: Sandra P. D9Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"78 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126297518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A017
Yasuhiro Shimizu, T. Yoshikawa, Kojima Takashi, K. Shoda, Kazuto Nosaka, S. Mizuno, S. Wada, Yuki Fujimoto, T. Sasada, Kenichi Kohashi, H. Bando, I. Endo, T. Nakatsura
Purpose: Heat shock protein 105 (HSP105) is overexpressed in a variety of human cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We identified HLA-A24 or A2-restricted HSP105 peptides that can induce HSP105 peptide-specific cytotoxic T lymphocytes (CTLs) (EP1536006, JP5112615, JP5291641, US9,404,925) and curried out a phase I clinical trial of HLA-A24 or A2-restricted HSP105 peptide vaccine in patients with CRC or EC (UMIN ID000017809). In this study, we aimed to demonstrate the immunological efficacy of the novel vaccine. Experimental design: 30 patients (HLA-A24 group; 15 patients, HLA-A2 group; 15 patients) with advanced CRC or EC were enrolled. Two types of vaccine (A24-1 and A24-7 or A2-7 and A2-12) were administered into the patients, matching HLA-types. Immunological responses were analyzed by ex vivo and in vitro IFN-γ ELISPOT assay using peripheral blood mononuclear cells before and after vaccination, and cytokines produced by HSP105-specific CTLs were measured by Cytometric Bead Array assay. We also analyzed the correlation between immunological responses and prognosis. Result: HSP105 peptide vaccines induced HSP105 peptide-specific CTLs in 15 of 30 patients. In HLA-A24 group, there were 7 patients with the induction only in ex vivo and almost all patients (n=13) showed skin reactions of vaccine sites. By contrast, in HLA-A2 group, there were 4 patients with the induction in ex vivo and 6 patients in in vitro, respectively, and only 6 patients with skin reactions of vaccine sites. In all patients, the existence of skin reaction correlated with the induction in ex vivo (p Citation Format: Yasuhiro Shimizu, Toshiaki Yoshikawa, Kojima Takashi, Kayoko Shoda, Kazuto Nosaka, Shoichi Mizuno, Satoshi Wada, Yuki Fujimoto, Tetsuro Sasada, Kenichi Kohashi, Hideaki Bando, Itaru Endo, Tetsuya Nakatsura. Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A017.
{"title":"Abstract A017: Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer","authors":"Yasuhiro Shimizu, T. Yoshikawa, Kojima Takashi, K. Shoda, Kazuto Nosaka, S. Mizuno, S. Wada, Yuki Fujimoto, T. Sasada, Kenichi Kohashi, H. Bando, I. Endo, T. Nakatsura","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A017","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A017","url":null,"abstract":"Purpose: Heat shock protein 105 (HSP105) is overexpressed in a variety of human cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We identified HLA-A24 or A2-restricted HSP105 peptides that can induce HSP105 peptide-specific cytotoxic T lymphocytes (CTLs) (EP1536006, JP5112615, JP5291641, US9,404,925) and curried out a phase I clinical trial of HLA-A24 or A2-restricted HSP105 peptide vaccine in patients with CRC or EC (UMIN ID000017809). In this study, we aimed to demonstrate the immunological efficacy of the novel vaccine. Experimental design: 30 patients (HLA-A24 group; 15 patients, HLA-A2 group; 15 patients) with advanced CRC or EC were enrolled. Two types of vaccine (A24-1 and A24-7 or A2-7 and A2-12) were administered into the patients, matching HLA-types. Immunological responses were analyzed by ex vivo and in vitro IFN-γ ELISPOT assay using peripheral blood mononuclear cells before and after vaccination, and cytokines produced by HSP105-specific CTLs were measured by Cytometric Bead Array assay. We also analyzed the correlation between immunological responses and prognosis. Result: HSP105 peptide vaccines induced HSP105 peptide-specific CTLs in 15 of 30 patients. In HLA-A24 group, there were 7 patients with the induction only in ex vivo and almost all patients (n=13) showed skin reactions of vaccine sites. By contrast, in HLA-A2 group, there were 4 patients with the induction in ex vivo and 6 patients in in vitro, respectively, and only 6 patients with skin reactions of vaccine sites. In all patients, the existence of skin reaction correlated with the induction in ex vivo (p Citation Format: Yasuhiro Shimizu, Toshiaki Yoshikawa, Kojima Takashi, Kayoko Shoda, Kazuto Nosaka, Shoichi Mizuno, Satoshi Wada, Yuki Fujimoto, Tetsuro Sasada, Kenichi Kohashi, Hideaki Bando, Itaru Endo, Tetsuya Nakatsura. Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A017.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"91 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122876533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A013
P. Lang, Tim Flaadt, M. Ebinger, P. Schlegel, H. Lode, R. Ladenstein, Anne-Marie Lang, Peter Ambross, J. Schaefer, J. Fuchs, H. Loibner, W. Schwinger, R. Handgretinger
Background: Pediatric patients with relapsed metastatic neuroblastomas have a poor prognosis and additional strategies are needed. We present results of a phase I/II-trial with subsequent immunotherapy with an anti-GD2mAb (CH14.18/CHO) after HLA-mismatched, haploidentical stem cell transplantation (SCT). Methods: T- and B-cell depleted stem cells from parental donors were used in combination with melphalan 140mg/m², thiotepa 10mg/kg, fludarabin 160mg/m² and ATG-F. CH14.18/CHOmAb was started on day 60-180 post-transplant: 6 cycles with 20mg/m²/day x 5; in cycles 4-6, 1x10 6 U/m² Interleukin 2 was given additionally. Disease status was evaluated with whole body MRI, MIBG scan and MRD detection in bone marrow aspirates. Primary endpoint was success of treatment, defined as a patient receiving the full protocol treatment, still alive 180 days after end of treatment without progression/unacceptable toxicity or severe GvHD. Results: 56 patients with 1st or ≥2nd metastatic relapse were enrolled. Disease status prior to antibody infusions was: CR (n=19), PR (n=31), mixed (n=6). 41% of patients with measurable tumor burden responded and reached CR after treatment. 90% of patients with initial CR could maintain this status. In total, success of treatment was observed in 60%. 3-year OS and EFS was 58% and 45%, respectively. Causes of death were: progression/relapse (25%) or TRM (7%). Factors of influence on EFS were (1) remission status prior to SCT (with CR, PR or mixed response resulting in 70%, 45% and 11% 3yEFS) and (2) bone marrow involvement prior to CH14.18 treatment (no MRD detectable: 60% 3yEFS vs. any MRD detectable: 20% 3yEFS). Frequent side effects were pain, fever, CRP elevation; rare side effects comprised SIRS/capillary leak syndrome, seizures, accommodation disturbances. Transient acute severe GvHD occurred in 1 patient. Conclusions: CH14.18/CHO infusions after haploidentical SCT are feasible with acceptable toxicity. Our results suggest an antitumor effect of the new, donor-derived immune system in combination with CH14.18 treatment. Citation Format: Peter Lang, Tim Flaadt, Martin Ebinger, Patrick Schlegel, Holger Lode, Ruth Ladenstein, Anne-Marie Lang, Peter Ambross, Juergen Schaefer, Joerg Fuchs, Hans Loibner, Wolfgang Schwinger, Rupert Handgretinger. Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A013.
背景:小儿复发性转移性神经母细胞瘤预后差，需要额外的治疗策略。我们介绍了一项I/ ii期试验的结果，在hla错配的单倍体干细胞移植(SCT)后，随后使用抗gd2mab (CH14.18/CHO)进行免疫治疗。方法:采用亲代供体T细胞和b细胞衰竭干细胞联合美法兰140mg/m²、硫替帕10mg/kg、氟达拉滨160mg/m²和ATG-F。移植后60-180天开始使用CH14.18/CHOmAb: 6个周期，20mg/m²/天x 5;在第4-6周期，额外给予1 × 10 6 U/m²白介素2。采用全身MRI、MIBG扫描和骨髓抽吸物MRD检测评估疾病状态。主要终点是治疗成功，定义为接受完整方案治疗的患者，在治疗结束后180天仍存活，无进展/不可接受的毒性或严重的GvHD。结果:56例第1次或≥2次转移性复发患者入组。抗体输注前疾病状态:CR (n=19)、PR (n=31)、混合型(n=6)。41%可测量肿瘤负荷的患者在治疗后缓解并达到CR。90%的初始CR患者可以维持这种状态。总的来说，治疗成功率为60%。3年OS和EFS分别为58%和45%。死亡原因为:进展/复发(25%)或TRM(7%)。影响EFS的因素有:(1)SCT前的缓解状态(CR、PR或混合反应导致70%、45%和11%的3yEFS)和(2)CH14.18治疗前的骨髓受累(未检测到MRD: 60% 3yEFS vs任何MRD: 20% 3yEFS)。常见的副作用是疼痛、发热、CRP升高;罕见的副作用包括SIRS/毛细血管渗漏综合征，癫痫发作，调节障碍。1例发生短暂急性严重GvHD。结论:单倍体SCT术后灌注CH14.18/CHO是可行的，且毒性可接受。我们的研究结果表明，新的供体来源的免疫系统与CH14.18治疗相结合具有抗肿瘤作用。引用格式:Peter Lang, Tim Flaadt, Martin Ebinger, Patrick Schlegel, Holger Lode, Ruth Ladenstein, Anne-Marie Lang, Peter Ambross, Juergen Schaefer, Joerg Fuchs, Hans Loibner, Wolfgang Schwinger, Rupert Handgretinger。单倍体干细胞移植及抗gd2抗体免疫治疗复发转移性神经母细胞瘤患者[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A013。
{"title":"Abstract A013: Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma","authors":"P. Lang, Tim Flaadt, M. Ebinger, P. Schlegel, H. Lode, R. Ladenstein, Anne-Marie Lang, Peter Ambross, J. Schaefer, J. Fuchs, H. Loibner, W. Schwinger, R. Handgretinger","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A013","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A013","url":null,"abstract":"Background: Pediatric patients with relapsed metastatic neuroblastomas have a poor prognosis and additional strategies are needed. We present results of a phase I/II-trial with subsequent immunotherapy with an anti-GD2mAb (CH14.18/CHO) after HLA-mismatched, haploidentical stem cell transplantation (SCT). Methods: T- and B-cell depleted stem cells from parental donors were used in combination with melphalan 140mg/m², thiotepa 10mg/kg, fludarabin 160mg/m² and ATG-F. CH14.18/CHOmAb was started on day 60-180 post-transplant: 6 cycles with 20mg/m²/day x 5; in cycles 4-6, 1x10 6 U/m² Interleukin 2 was given additionally. Disease status was evaluated with whole body MRI, MIBG scan and MRD detection in bone marrow aspirates. Primary endpoint was success of treatment, defined as a patient receiving the full protocol treatment, still alive 180 days after end of treatment without progression/unacceptable toxicity or severe GvHD. Results: 56 patients with 1st or ≥2nd metastatic relapse were enrolled. Disease status prior to antibody infusions was: CR (n=19), PR (n=31), mixed (n=6). 41% of patients with measurable tumor burden responded and reached CR after treatment. 90% of patients with initial CR could maintain this status. In total, success of treatment was observed in 60%. 3-year OS and EFS was 58% and 45%, respectively. Causes of death were: progression/relapse (25%) or TRM (7%). Factors of influence on EFS were (1) remission status prior to SCT (with CR, PR or mixed response resulting in 70%, 45% and 11% 3yEFS) and (2) bone marrow involvement prior to CH14.18 treatment (no MRD detectable: 60% 3yEFS vs. any MRD detectable: 20% 3yEFS). Frequent side effects were pain, fever, CRP elevation; rare side effects comprised SIRS/capillary leak syndrome, seizures, accommodation disturbances. Transient acute severe GvHD occurred in 1 patient. Conclusions: CH14.18/CHO infusions after haploidentical SCT are feasible with acceptable toxicity. Our results suggest an antitumor effect of the new, donor-derived immune system in combination with CH14.18 treatment. Citation Format: Peter Lang, Tim Flaadt, Martin Ebinger, Patrick Schlegel, Holger Lode, Ruth Ladenstein, Anne-Marie Lang, Peter Ambross, Juergen Schaefer, Joerg Fuchs, Hans Loibner, Wolfgang Schwinger, Rupert Handgretinger. Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A013.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126386909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A018
J. Merchan, J. Rodón, Derek Ostertag, S. Venkat, A. Donahue, P. Horner, Dalissa Tijera, T. Kheoh, D. Jolly, H. Gruber, J. Shorr, G. Falchook
Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector that selectively infects cancer cells due to cell division requirements for virus integration into the genome, and defects in innate and adaptive immune responses found in malignant tissues that support virus replication. Toca 511 spreads through cancer cells and stably delivers optimized yeast cytosine deaminase (CD) that, upon administration of the prodrug, Toca FC (an investigational, extended-release version of 5-fluorocytosine [5-FC]), converts 5-FC into 5-fluorouracil (5-FU). 5-FU kills infected dividing cancer cells and diffuses to and kills surrounding cells in the tumor microenvironment, including immunosuppressive myeloid cells. In animal models, this depletion of immunosuppressive myeloid cells leads to therapeutically active immunity against tumors. A similarly derived antitumor response may occur in cancer patients, as local injection of Toca 511 into the tumor bed after resection of recurrent high-grade glioma followed by treatment with Toca FC has been associated with prolonged survival and durable complete responses (median duration of follow-up: 37.4+ months); responses were delayed in onset, consistent with time to response for immuno-oncology agents. The current phase 1b, multicenter, open-label study (Toca 6; NCT02576665) is designed to investigate changes in immune activity after treatment with Toca 511 and Toca FC in patients with advanced malignancies. Toca 511 is administered intravenously (IV) daily for 3 days and then as a single injection into metastatic or recurrent tumor. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Biopsies are obtained prior to and following exposure to Toca 511 and Toca FC treatment to evaluate changes in immune activity, and peripheral blood is obtained contemporaneously for evaluation. The study has enrolled 19 patients to date (colorectal cancer: 15; sarcoma: 2; non-small cell lung and pancreas cancer: 1 each). Treatment has been well tolerated. Viral RNA, DNA, and CD protein expression are observed in tumor after IV delivery of Toca 511. We plan to report on tumor microenvironment remodeling that follows treatment with Toca 511 and Toca FC. Infiltrating T-cell subpopulations, B cells, and monocytes quantified by immunofluorescence from stained formalin-fixed, paraffin-embedded samples will be presented. Additionally, changes in peripheral blood, including T-cell effector, helper/memory, and regulatory populations, and myeloid lineage cells following exposure to Toca 511 alone and following subsequent exposure to Toca FC will be reported. Data from this study will inform future development of Toca 511 and Toca FC alone or in combination with other therapies in patients with solid tumors. Citation Format: Jaime Merchan, Jordi Rodon, Derek Ostertag, Shree Venkat, Arthur Donahue, Peder Horner, Dalissa Tijera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S.
Toca 511 (vocimagene amiretrorepvec)是一种有条件裂解的逆转录病毒复制载体，由于细胞分裂需要病毒整合到基因组中，以及在恶性组织中发现的支持病毒复制的先天和适应性免疫反应缺陷，它选择性地感染癌细胞。Toca 511在癌细胞中扩散，稳定地递送优化的酵母胞嘧啶脱氨酶(CD)，在给予前药Toca FC(一种5-氟胞嘧啶的缓释版本[5-FC])后，将5-FC转化为5-氟尿嘧啶(5-FU)。5-FU杀死被感染的正在分裂的癌细胞，并扩散到肿瘤微环境中的周围细胞，包括免疫抑制的髓细胞。在动物模型中，这种免疫抑制骨髓细胞的耗竭导致对肿瘤的治疗活性免疫。癌症患者也可能出现类似的抗肿瘤反应，在复发性高级别胶质瘤切除术后局部注射Toca 511，再用Toca FC治疗，可以延长生存期和持久的完全缓解(中位随访时间:37.4个月以上);反应延迟，与免疫肿瘤药物的反应时间一致。目前的1b期多中心开放标签研究(Toca 6;NCT02576665)旨在研究晚期恶性肿瘤患者接受Toca 511和Toca FC治疗后免疫活性的变化。Toca 511每天静脉注射(IV) 3天，然后单次注射到转移性或复发性肿瘤。口服Toca FC在4周后开始，每4-6周重复一次。暴露于Toca 511和Toca FC治疗之前和之后进行活组织检查，以评估免疫活性的变化，同时获得外周血以进行评估。迄今为止，该研究已招募了19名患者(结直肠癌:15名;肉瘤:2;非小细胞肺癌和胰腺癌各1例)。治疗的耐受性良好。静脉给药Toca 511后，观察肿瘤组织中病毒RNA、DNA和CD蛋白的表达。我们计划报道Toca 511和Toca FC治疗后的肿瘤微环境重塑。浸润t细胞亚群，B细胞和单核细胞通过免疫荧光定量从染色的福尔马林固定，石蜡包埋的样品将被介绍。此外，将报道单独暴露于Toca 511和随后暴露于Toca FC后外周血的变化，包括t细胞效应、辅助/记忆和调节群体以及髓系细胞。这项研究的数据将为Toca 511和Toca FC单独或与其他治疗联合用于实体瘤患者的未来发展提供信息。引文格式:Jaime Merchan, Jordi Rodon, Derek Ostertag, Shree Venkat, Arthur Donahue, Peder Horner, Dalissa Tijera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S. Shorr, Gerald S. Falchook。Toca 511和Toca FC对晚期恶性肿瘤患者肿瘤微环境及外周血群的影响[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A018。
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