Clinical Trials of Cancer Immunotherapies最新文献

{"title":"Abstract A021: Vaccination with autologous, nonattenuated, live glioblastoma cells induces potent peripheral and intratumoral anti-tumoral responses: A first-in-human study","authors":"I. Volovitz, N. Shapira, R. Grossman, Z. Ram","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A021","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A021","url":null,"abstract":"Glioblastoma (GBM), which grows uninhibited in the brain, almost never metastasizes outside of it. The rare occurrence ( 9 months) approximately 50% of rats challenged with F98 cells intracranially. The results in the F98 model were corroborated in the CNS1 astrocytoma model in Lewis rats. The fraction of cured rats in both models were the highest reported in published literature. We found that the spontaneous rejection of live glioma cells inoculated in peripheral sites was immune-mediated. This location-biased immune response was termed “Split Immunity”—a tumor that thrives in an immune-privileged site (e.g., the brain) may be inhibited by injecting live unmodified tumor cells in a site that is not privileged, generating protective immunity that spreads back to the privileged site.To evaluate the applicability of the “Split Immunity” approach in humans, we ran a first-in-human (FIH) study on two recurrent GBM patients. The patients were vaccinated subcutaneously, initially with autologous irradiated tumor cells, and then with autologous, non-attenuated, live tumor cells. The treatment caused no serious adverse events. The injected live tumor cells did not grow at the inoculation site, nor did they spread metastatically, as evaluated by choline 18F PET-CT. Standard biochemical and hematologic blood tests showed no treatment-related adverse effects. Both patients’ quality of life (QoL) questionnaires demonstrated subjective improvements in self-evaluated “global health status.” The treatment had demonstrated several signs indicative of efficacy. MRI evaluation using “treatment response assessment maps” (TRAM) demonstrated strong increases in the “treatment-response” component following live-cell vaccination, compatible with “pseudo-progression-like” responses in both patients. Using elaborate 8-color flow cytometric panels, we detected potent tumor-cell specific polyfunctional activation in 2.5% and 5% of peripheral cytotoxic T-cell (CTL) and T helper cells (Th), respectively, 3 days following live-cell vaccination. Flow cytometric immune mapping of all intratumoral immune cell subsets showed major changes from baseline that had occurred shortly after live-cell vaccinations. We observed major increases (8 to 200 fold) in both patients of all monitored intratumoral dendritic cell (DC) subsets (CD1c+ and CD141+ myeloid DC, CD123+ plasmacytoid DC). Patient-1 showed the highest frequency of intratumoral CD56brt natural killer (NK) cells from all previously fully mapped brain tumor patients. Patient-2’s intratumoral CTL and Th were increase by 6- and 17-fold, respectively. Patient-2’s CD141+ and CD1c+ myeloid DC had exhibited upregulated CD86 maturation marker following treatment. Overall, the immune infiltrate following treatment in Patient-2 exceeded the immune infiltrates found in 42 previously fully-mapped brain tumor patients. The flow cytometric results were corroborated by the patients’ immunohistochemistry data. Patient-2, who had been treated","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"77 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":"114793770","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}

{"title":"Abstract A001: Phase I study of vaccine therapy with a cocktail of peptides for pediatric patients with refractory solid tumors","authors":"Yu Akazawa, A. Hosono, T. Yoshikawa, Hideo Kaneda, J. Hara, Y. Kinoshita, Kenichi Kohashi, A. Manabe, Y. Shioda, K. Shoda, M. Shimomura, S. Mizuno, Y. Nakamoto, T. Nakatsura","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A001","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A001","url":null,"abstract":"Recently, the aggressive intervention of multidisciplinary therapy has resulted in improving the life prognosis of pediatric solid tumors. However, in the pediatric patients with metastatic or refractory solid tumors, the prognosis remains poor. Additionally, various critical, late complications could continue to occur. Therefore, the development of novel, effective therapy is urgently required. Immunotherapy could be the one of effective therapeutic strategy for pediatric solid tumors. Actually, the KOC1, FOXM1, and KIF20A might be capable of being an ideal target of anticancer immunotherapy against pediatric solid tumors that highly had expression of these cancer antigens. In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of NCCV cocktail 1 vaccine, a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric solid tumors. Experimental Design: Twelve patients with refractory pediatric solid tumors, including 3 patients with neuroblastoma, 2 patients with Ewing’s sarcoma, 5 patients with rhabdomyosarcoma, and 2 patients with osteosarcoma, underwent NCCV cocktail 1 vaccination (intradermal injections every a week). In 9 enrolled patients, the histologic expression of KOC1, FOXM1, and KIF20A before vaccination were evaluated using tissue specimen obtained from biopsy or surgery. The primary endpoint was the safety of NCCV cocktail 1 vaccination. The secondary endpoints were immune response, as measured by in vivo and in vitro interferon (IFN)-r enzyme-linked immunospot (ELISPOT) assay and Dextramer assay, and the clinical outcomes of tumor response and progression free survival (PFS).Results:No dose-limiting toxicity (DLT) was observed in this trial, and we suggested that NCCV cocktail 1 vaccination was well-tolerated. Of nine patients, 6 patients (66.7%), 6 patients (66.7%), and 7 patients (77.8%), exhibited positive expression of KOC1, FOXM1, and KIF20A before vaccination, respectively. Of eleven patients, 4 patients (36.4%), 8 patients (72.7%), and 5 patients (45.5%) were induced peptide-specific CTL response of KOC, FOXM1, and KIF20A by NCCV cocktail 1 vaccine, respectively. Also, 4 patients showed stable disease after 8 weeks, and 2 patients showed during of remission for more than 11 months after second complete remission. Additionally, patients with high peptide-specific CTL frequencies of all KOC, FOXM1, and KIF20A (n=4) had better PFS than those with low frequencies (n=7) by Kaplan-Meier analysis (log-rank test, P =0.019). By Cox proportional hazard models, univariate and multivariate analysis indicated that only induction of peptide specific CTL in all of these three antigens was independent factor related to PFS (P = 0.039; HR = 5.60; 95% CI 1.09-28.91, P = 0.050; HR = 6.00; 95% CI 1.00-36.32, respectively). Conclusions:The results of this trial demonstrated that the NCCV cocktail 1 vaccine was safe and had ability to induce some degree of immune response, wh","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"10 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":"127913264","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}

{"title":"Abstract A020: Immunomonitoring for actively personalized peptide vaccines (APVACs) during immunotherapeutic treatment of glioblastoma","authors":"Alexander Ulges, N. Hilf, W. Wick, M. Plattén, P. Dietrich, K. Frenzel, A. Admon, S. H. Burg, A. Deimling, P. Straten, C. Gouttefangeas, J. Kroep, F. Martínez-Ricarte, H. Okada, C. Ottensmeier, B. Ponsati, H. Poulsen, S. Stevanović, G. Tabatabai, H. Rammensee, U. Şahin, D. Maurer, R. Mendrzyk","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A020","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A020","url":null,"abstract":"Cancer immunotherapy to gliomas has so far failed to show encouraging results, as gliomas are rarely mutated and show various mechanisms of immune escape. To improve therapy to these type of cancer, the Glioma Actively Personalized Vaccine Consortium (GAPVAC) integrated a highly personalized peptide vaccine approach into glioblastoma standard of care treatment combining neoepitope and nonmutated tumor antigens to exploit the full repertoire of tumor antigens. In this phase I clinical trial fifteen patients received two different types of personalized peptide vaccines (APVAC1 and APVAC2), that were selected based on transcriptome, immunopeptidome and mutational analysis of the patient’s individual tumors. While APVAC1 vaccines were composed of nonmutated tumor antigens selected in a warehouse-based approach, APVAC2 vaccines primarily targeted neoepitopes. Both vaccines were used in combination with poly-ICLC and GM-CSF as adjuvants and demonstrated expected safety profile and outstanding Immunogenicity. Immunomonitoring of APVAC1 peptides was carried out using a combinatorial ex vivo Class I 2D multimer (2DMM) and Class II intracellular cytokine staining (ICS) assay with an outstanding sensitivity to detect even one peptide-specific cell in one million of CD4 or CD8 T-cells. Nonmutated APVAC1 class I peptides showed induction of persistent CD8 T-cell responses, mainly consisting of a highly favorable central memory phenotype (CM). Furthermore, APVAC1 class II peptides demonstrated induction of polyfunctional CD4 T-cells predominantly of a type 1 T helper cell (TH1) phenotype. Notably, an APVAC1 class II specific T-cell response was detected in tumor-infiltrating lymphocyte (TIL) fraction obtained from resection of one patient. On the other side, immune responses to APVAC2 peptides were analyzed using a pan-ICS assay including a single in vitro sensitization step to analyze a broad array of cytokines produced by CD4 T helper (TH) cells and CD8 CTLs in parallel. APVAC2 peptides showed excellent immunogenicity and induced potent and multifunctional CD4 T-cell responses, mostly of a TH1 phenotype that often concurred with CTL responses. Furthermore, the induction of APVAC1-specific CD8 memory cells, as a marker for the potency of the vaccine-induced immune responses, reversely correlated with the baseline frequencies of regulatory T-cells (Treg). Taken together, actively personalized peptide vaccines (APVACs) were highly immunogenic and induced sustained responses of a highly favorable CD4 and CD8 T-cell phenotype. The vaccination showed the expected safety profile and the approach was feasible, even in this highly individualized setting. Therefore, the APVAC vaccination approach clearly represents a step forward on the path to bring the benefit of immunotherapy to glioblastoma patients. Citation Format: Alexander Ulges, Norbert Hilf, Wolfgang Wick, Michael Platten, Pierre-Yves Dietrich, Katrin Frenzel, Arie Admon, Sjoerd S.H. van der Burg, Andreas vo","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"10 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":"124963536","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}

{"title":"Abstract A009: Forty-three week follow-up of a phase 1a clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients","authors":"J. Head, G. Daniels, M. McKinney, J. Wang-Rodriguez","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A009","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A009","url":null,"abstract":"While progress has occurred in both cellular and immune checkpoint therapy, the benefit of therapeutic cancer vaccines has been difficult to demonstrate. Prostate cancer may be an exception with the modest activity of Sipuleucel T. We have developed a potentially low cost and easy to administer therapeutic vaccine with the combination of tumor antigen (PSA) and biologic adjuvants (IL2 and GM-CSF). This study is a phase 1a clinical trial of a PSA/IL-2/GM-CSF vaccine in biochemically recurrent hormone-naive and hormone-independent prostate cancer patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of serious adverse events (SAEs) and dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients enrolled and nineteen patients completed all six intradermal injections (one patient received 5 vaccines, missed week 11 vaccine) of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. None of the patients vaccinated in the phase 1a portion had an SAE or DLAE with the most common AE relating to grade 1 injection site reactions. Fifteen of the 18 patients who received vaccines had immune responses to PSA as demonstrated in a lymphocyte blastogenesis assay by week 31. Interestingly, after vaccination 14 of 20 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the growth of the prostate cancer. Five of 20 patients have progressed (3 PSA progression and 2 radiologic progression) at 43 weeks’ follow-up. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Jessica Wang-Rodriguez. Forty-three week follow-up of a phase 1a clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients [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 A009.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"75 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":"133162390","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}

{"title":"Abstract A016: PEGylated IL-10 (pegilodecakin) induces systemic immune activation, CD8+ T-cell invigoration and polyclonal T-cell expansion in cancer patients","authors":"M. Oft, A. Naing, J. Infante, K. Papadopoulos, I. Chan, Cong Shen, Navneet Ratti, K. Autio, D. Wong, M. Patel, P. Ott, G. Falchook, S. Pant, A. Hung, J. Mumm, Matthew Adamow, S. McCauley, R. Verma, P. Wong, Peter VanVlasselaer, J. Leveque, N. Tannir","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A016","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A016","url":null,"abstract":"Background: Immune therapies rely on successful activation of systemic immunity as well as expansion of the T-cell clones for tumor regression and successful therapeutic outcomes. PEGylated IL-10 (pegilodecakin or AM0010) monotherapy has been reported to achieve 25% objective tumor responses (ORR) in intermediate to poor risk renal cell cancer (RCC) in median 4th line of treatment (LOT) (range 1-8) (Naing A et al, JCO 2016). Here we report the immunological underpinnings of pegilodecakin induced tumor responses alone and in combination with anti-PD-1. Methods: Samples were collected post written consent from patients enrolled in a multi-basket trial (NCT0200944) and were analyzed in accordance with the IRB. Patients on AM0010 alone administered daily self-injection of pegilodecakin at 20 µg/kg, SC. Patients in the pembrolizumab + pegilodecakin received in addition pembrolizumab at 2mg/kg IV, Q3W. Normal healthy volunteers (NCT03267732) received a single (day 1) and multiple doses (days 4-9) of 5 µg/kg or 10 µg/kg AM0010 SC. Systemic and cellular antitumor immune responses were assessed by serum cytokine analysis (luminex) and by PBMC flow cytometry respectively. Additionally, immune fluorescence (IF) or immunohistochemistry was performed on formaldehyde fixed archival, pretreatment biopsies and on treatment biopsies CD8, granzyme B, phospho-STAT-3 or LAG-3, T-bet/CD3 and HLA-A. T-cell clones were quantified by TCR deep sequencing (Adaptive biotechnology) from DNA isolated using EDTA blood samples. Results: Pegilodecakin treatment induced a systemic anti-tumor immune cytokine response biased towards Th1 & Th2 cytokines (IFNg, IL-18, TNFa, IL-3, IL-4) along with IL-7. Tuppressive (TGFb) and Th17 cytokines (IL-23, IL-17) were reduced. Cytotoxic effector molecules (Granzyme B, FasL, lymphotoxinB) were increased in the serum. PBMC analysis by flow cytometry in pre- and post-treatment samples show invigoration of the exhausted, T-cells, with increased proliferative index among CD8+ T-cells expressing LAG3 and PD1 throughout pegilodecakin treatment. The increase of PD-1+ Lag-3+ Ki-67+ CD8+ T-cells correlates with objective response to AM0010. On-treatment biopsies showed that pegilodecakin increased GzmB+, Phospho-Stat3+, Lag-3+ CD8+ T-cells in the tumor. T-cell clonal analysis by TCR sequencing on PBMCs from patients during pegilodecakin treatment showed expansion of several hundred previously undetected T-cell clones per patient. Expansion of these T-cell clones in the blood correlated with tumor response, with patients with objective response showing increased number of novel clones as compared to patients with progressive disease. Conclusion: We report that pegilodecakin treatment induced a systemic Th1 immune activation with reduction of Th17 related cytokines. We further report the hallmarks of CD8+ T-cell immunity in these cancer patients, including the systemic elevation of IFNg and GranzymeB levels, expansion and activation of CD8+ TILs, and th","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"76 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"120919351","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}

{"title":"Abstract A015: Cellular immunomonitoring for personalized adoptive cellular therapy trial ACTolog® (IMA101-101)","authors":"R. Mendrzyk, Alexander Ulges, T. Demberg, G. Stephens, C. Reinhardt, S. Walter, D. Maurer","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A015","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A015","url":null,"abstract":"Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g., only one target is addressed), or iii) off-target toxicities (e.g., expression of targets on normal tissues). ACTolog® concept, utilizing antigen specific T-cells (IMA101), identified by the Immatics’ proprietary XPRESIDENT® technology, is intended to overcome these limitations by introducing multiple novel tumor targets. ACTolog® is a personalized ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Target positive tumors are identified by qPCR. Expression levels predictive for antigen presentation are determined by mass spectrometry. Autologous T-cells against ACTolog targets are in vitro primed in the presence of IL-21 followed by HLA tetramer-guided cell sorting and expansion prior to infusion. IMA101-101 is a first-in-human clinical trial in HLA-A*02:01 positive patients with relapsed or refractory solid tumors using the multitargeted ACTolog® approach in which up to four products with different tumor target-specificities are manufactured and infused for each patient. We developed two flow cytometric phenotyping assays that allow us to determine the frequency of target-specific cells in the final product and persisting cells in the blood as well as to deeply characterize the memory marker expression (CD45RA, CCR7, CD27, CD28, CD45RO, CD62L, CD57, CD127) and immune checkpoint expression (CD137, LAG-3, PD-1, TIGIT, TIM-3) of target-specific cells. Product characterization and initial persistence data of the three first treated patients revealed a high prevalence of persisting target-specific cells in the blood until 2 months after infusion as well as a favorable phenotype of target-specific cells. At the conference 6 months’ data for one patient will be available and presented. Citation Format: Regina Mendrzyk, Alexander Ulges, Thorsten Demberg, Geoffrey Stephens, Carsten Reinhardt, Steffen Walter, Dominik Maurer. Cellular immunomonitoring for personalized adoptive cellular therapy trial ACTolog® (IMA101-101) [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 A015.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"24 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":"124077566","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}

{"title":"Abstract A019: Longitudinal analysis of the landscape of cancer trials testing anti-PD-1/L1 monoclonal antibodies","authors":"Jun Tang, L. Pearce, Jill O’Donnell-Tormey, Vanessa M. Hubbard-Lucey","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A019","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A019","url":null,"abstract":"Background: Monoclonal antibodies targeting PD-1 or PD-L1 (PDx) have revolutionized the standards of care for many types of cancer. As of June 2018, 5 anti-PDx agents have been approved by the FDA as monotherapy or part of combination therapy to treat 13 different cancer types. Since the first anti-PDx trial started in 2006, the anti-PDx clinical trial landscape has dramatically evolved. A current understanding of this expanding landscape by stakeholders in the immunotherapy clinical development enterprise will help to inform their prioritization of clinical trials and to support more efficient and effective evaluation of promising treatments. Methods: The Cancer Research Institute, a leading nonprofit organization dedicated to cancer immunotherapy research, has been tracking the progress in the immuno-oncology space over the past 5 years. Having analyzed the database at Clinicaltrials.gov, we were able to compare the available information regarding new interventional cancer trials evaluating PDx with that of all interventional cancer trials. We also compared the current PDx trial landscape with our previous PDx trial analysis conducted in Sept. 2017. Results: In the past decade, the new interventional cancer trials started per year have gradually increased from 2,294 in 2008 to 3,727 in 2017. However, during the same period of time, the number of new PDx trials per year increased from one in 2008 to 776 in 2017. Significantly, PDx trials accounted for 21% of all new interventional cancer trials in 2017. While the number of new trials increased, the average planned patient enrollment per PDx trial decreased from 476 patients in 2011 to 132 patients in 2017. When compared with our previous landscape analysis conducted in Sept. 2017, we found the number of active PDx trials (including both monotherapy and combination) increased from 1,502 as of Sept. 2017 to 2,011 as of Jun 2018, and the number of active PDx combination trials increased from 1,105 to 1,449 during the same time. Finally, in addition to PD-1 or PD-L1, other cancer targets evaluated by those PDx combination trials have expanded from 166 as of Sept. 2017 to 266 as of June 2018, and the planned patient enrollment of these combination trials expanded from 165,215 to 225,747 accordingly. Conclusion: Our landscape analyses show that the PDx trial space has been rapidly expanding, and the numbers of new trials started per year suggest no indication of slowing down in the near future. The 2,011 ongoing PDx trials are a testament to the field’s commitment to developing more effective immunotherapies that will build on the success of PDx checkpoint inhibitors. Care should be given, however, to ensure the trials being conducted are testing new PDx therapies or expanding the effectiveness of PDx therapies to new cancer types while avoiding the concentration of trials testing similar PDx therapies in a few identical cancer conditions. Citation Format: Jun Tang, Laura Pearce, Jill O9Donnell-Tormey","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"45 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":"124761467","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}

{"title":"Abstract A022: Phase 1/2 study to evaluate systemic durvalumab (durva) + intraperitoneal ONCOS-102 in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC)","authors":"D. Zamarin, K. Odunsi, B. Slomovitz, Vanessa M. Hubbard-Lucey, D. McCabe, L. Shohara, P. Schwarzenberger, T. Ricciardi, M. Macri, A. Ryan, A. Aksnes, L. Kuryk, R. Venhaus","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A022","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A022","url":null,"abstract":"Metastasis to the peritoneal cavity is associated with end-stage disease in many cancers, including epithelial ovarian cancer (OC) and colorectal cancer (CRC), both of which exhibit poor responses to checkpoint inhibitors. Oncolytic viruses may promote tumor recognition by the immune system. Evidence suggests that locoregional treatment with oncolytic viruses can be used to improve the efficacy of checkpoint inhibitors at both treated and distant tumor sites. ONCOS-102 is an oncolytic adenovirus encoding for granulocyte-macrophage colony stimulating factor (GMCSF). Durvalumab (durva), a checkpoint inhibitor, is a human IgG1 monoclonal antibody against programmed cell death ligand-1 (PD L1). This study evaluates the combination of intraperitoneally administered ONCOS-102 with systemic durva in patients with peritoneal disease who have histologically confirmed OC or metastatic CRC and have failed prior standard therapies.This ongoing phase 1/2, open-label study (NCT02963831) evaluates the safety and antitumor/biologic activity of durva (1500 mg intravenous, every 4 weeks x 12) + ONCOS-102 (intraperitoneal, weekly x 6); cyclophosphamide is given before the first ONCOS-102 dose. Phase 1 will follow a 3+3 design to evaluate the ONCOS 102 dose to be given with durva. Phase 2 will evaluate the activity of the combination using Simon’s 2-stage MINIMAX design. In Stage 1, the OC and CRC cohorts will enroll 18 and 13 patients, respectively. If ≥ 5 patients in the OC cohort or ≥ 1 patient in the CRC cohort are progression free at the end of Week 24 (PFS24W), then Stage 2 will enroll 15 and 14 additional patients in the OC and CRC cohorts for a total n of 33 and 27, respectively. The null/alternative hypotheses for PFS24W are 20/40% for OC and 5/20% for CRC. The null hypothesis will be rejected if ≥ 11 patients in the OC cohort or ≥ 4 patients in the CRC cohort experience PFS24W. The primary endpoints are safety/tolerability per Common Terminology Criteria for Adverse Events (CTCAE) for phase 1 and PFS24W rate by RECIST 1.1 for phase 2. Secondary endpoints are safety and tolerability, response rate at 8 and 24 weeks, progression-free survival, and overall survival. Exploratory endpoints are immunologic effects in tumors and peripheral blood. Enrollment opened 07 September 2017. As of 27 June 2018, 4 patients are enrolled; enrollment is ongoing. Citation Format: Dmitriy Zamarin, Kunle Odunsi, Brian Slomovitz, Vanessa M. Hubbard-Lucey, Danielle McCabe, Lisa Shohara, Paul Schwarzenberger, Toni Ricciardi, Mary Macri, Aileen Ryan, Anne-Kirsti Aksnes, Lukasz Kuryk, Ralph Venhaus. Phase 1/2 study to evaluate systemic durvalumab (durva) + intraperitoneal ONCOS-102 in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC) [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): AAC","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"33 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":"131458156","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}

{"title":"Abstract A003: Safety and preliminary efficacy of ACTR707, autologous T lymphocytes expressing an antibody-coupled T-cell receptor, in combination with rituximab in subjects with relapsed or refractory CD20-positive B-cell lymphoma","authors":"V. Bachanova, Jonathon B. Cohen, L. Akard, S. Jaglowski, J. Sachs, A. Ranger, Patricia L. Harris, Kathleen E. McGinness, Greg T. Motz, I. Flinn","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A003","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A003","url":null,"abstract":"Background: Autologous T cells engineered to express a universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res 2014]. ACTR707 was identified through rigorous preclinical screening of more than 100 different ACTR variants. It is composed of the extracellular domain of CD16, the cytoplasmic signaling domain of CD3ζ, and the costimulatory domain of CD28. Study ATTCK-20-03 (NCT03189836) is the first clinical trial of ACTR707. ACTR707 in combination with rituximab is being studied in subjects with relapsed or refractory CD20+ B-cell lymphoma previously treated with anti-CD20 monoclonal antibody (mAb) therapy. Herein we report data from the first dose level of ACTR707, where 6 subjects have been enrolled and treated.Methods: ATTCK-20-03 is a first-in-human, multicenter phase 1 dose escalation study of ACTR707 in combination with rituximab. The primary objective is to evaluate the safety of ACTR707 in combination with rituximab, and secondary objectives include evaluation of antitumor activity, assessment of T-cell expansion and persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory aggressive CD20+ B-cell lymphoma of DLBCL, MCL, PMBCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb therapy in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and a single infusion of ACTR707. Additional doses of rituximab are administered, one dose every 3 weeks in the absence of disease progression. The study is separated into two sequential phases, a dose escalation and a safety expansion phase. During dose escalation, ACTR707 will be tested at increasing doses in combination with rituximab. Results: Six subjects received ACTR707 in combination with rituximab at the first dose level: 5 diagnosed with DLBCL (83%) and 1 with Gr3b FL (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥ 3 lines of prior therapy, and 67% had no response to or progression within 6 months of immediate prior therapy. ACTR707 was successfully manufactured for all subjects. ACTR+ T cells demonstrated expansion and were detectable at D28 post-ACTR707 infusion for all subjects tested. There were no dose-limiting toxicities observed in the 4 subjects evaluable for DLTs (2 subjects were not DLT-evaluable due to early disease progression). There were no serious adverse events of cytokine release syndrome, neurotoxicity, or autoimmune events and no deaths on study. Grade 3 or higher AEs included neutropenia (n=2), febrile neutropenia (n=2), and thrombocytopenia (n=1). Antitumor activity was assessed in all 6 subjects. Three subjects experienced disease progression and 3 subjects demonstrated investigator-reported complete responses at the first disease response assessment (D42","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"24 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":"134574582","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}

{"title":"Abstract A004: HER2 cancer vaccine phase I clinical trial shows clinical benefit in 54% of evaluable patients","authors":"J. Berzofsky, L. Wood, Hoyoung M. Maeng, J. Trepel, D. Stroncek, J. Morris","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A004","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A004","url":null,"abstract":"We developed and tested in mice and human patients a therapeutic cancer vaccine targeting HER2-expressing cancers comprising autologous dendritic cells (DCs) transduced with an adenovirus expressing the non-signaling extracellular and transmembrane domains of HER2, a driver oncogene in many cancers including breast, ovarian, lung, colorectal, gastroesophageal, and bladder, and others. In mice, the homologous vaccine cured virtually all mice with large established tumors up to 2 cm and with established macroscopic lung metastases, and the protection was dependent on antibodies to HER2 that inhibited HER2 phosphorylation, but was FcR (ADCC) independent, and thus distinct from the main recognized mechanism of the clinically-approved anti-HER2 monoclonal antibody, trastuzumab. We are carrying out a phase I clinical trial in patients with advanced metastatic cancers who had progressed on treatment with at least one line of standard therapy, with tumors that are HER2 1+, 2+ or 3+ by immunohistochemistry or have a HER2 FISH score ≥ 1.8. Part 1 of the trial was carried out in patients naive to trastuzumab or other HER2-directed therapies, to be able to demonstrate safety in the absence of complicating effects of prior HER2-targeted therapies. In Part 1, although no responses were seen in 6 patients at the lowest dose of 5 million DCs, at the second and third dose escalations (10 and 20 million DCs), of 11 evaluable patients, 6 (54%) had clinical benefit, including one complete response (CR) lasting 89 weeks, one partial response (PR) lasting 24 weeks, and 4 cases of stable disease (SD), seen in patients with metastatic ovarian, gastroesophageal, prostate or colorectal cancers. Adverse reactions were mainly injection site reactions that generally did not require treatment. Serial echocardiograms did not reveal any evidence of cardiotoxicity. The number of circulating tumor cells also decreased in 40% (8/20), 83% (5/6) and 100% (2/2) at 12, 28 and 48 weeks on study, respectively. Based on these results and safety data, the FDA and IRB approved increasing the maximum dose to 40 million DCs and opening Part 2 of the trial in patients who have progressed after prior HER2-directed therapies such as trastuzumab, mostly metastatic breast and gastric cancer patients. Early results in Part II already showed 2 patients with SD. Thus, we have translated a cancer vaccine from mice to human clinical trials with very promising early results, and intend to combine this vaccine with checkpoint inhibitors, as vaccines can induce T-cell responses that turn “cold” tumors into “hot” ones amenable to checkpoint blockade immunotherapy. Citation Format: Jay A. Berzofsky, Lauren V. Wood, Hoyoung Maeng, Jane Trepel, David Stroncek, John C. Morris. HER2 cancer vaccine phase I clinical trial shows clinical benefit in 54% of evaluable patients [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":"36 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":"130132431","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}