Clinical Cancer Research最新文献

Purpose: Activating T-cell costimulatory receptors is a promising approach for cancer immunotherapy. In preclinical work, adding an OX40 agonist to in situ vaccination with SD101, a TLR9 agonist, was curative in a mouse model of lymphoma. We sought to test this combination in a phase I clinical trial for patients with low-grade B-cell lymphoma.

Patients and methods: We treated 14 patients with low-dose radiation, intratumoral SD101, and intratumoral and intravenous BMS986178, an agonistic anti-OX40 antibody. The primary outcome was safety. Secondary outcomes included overall response rate and progression-free survival.

Results: Adverse events were consistent with prior experience with low-dose radiation and SD101. No synergistic or dose-limiting toxicities were observed. One patient had a partial response, and nine patients had stable disease, a result inferior to our experience with TLR9 agonism and low-dose radiation alone. Flow cytometry and single-cell RNA sequencing of serial tumor biopsies revealed that T and NK cells were activated after treatment. However, high baseline OX40 expression in T follicular helper and T regulatory type 1 cells, as well as high posttreatment soluble OX40, shed from these T cells upon activation, associated with progression-free survival of less than 6 months.

Conclusions: Clinical results of T-cell costimulatory receptor agonism have now repeatedly been inferior to the motivating preclinical results. Our study highlights potential barriers to clinical translation, particularly differences in preclinical and clinical reagents and the complex biology of these coreceptors in heterogeneous T cell subpopulations, some of which may antagonize immunotherapy.

Antibodies targeting immune checkpoints, such as PD-1, PD-L1, or CTLA-4, have transformed the treatment of patients with lung cancers. Unprecedented rates of durable responses are achieved in an imperfectly characterized population of patients with metastatic disease. More recently, immune checkpoint inhibitors have been explored in patients with resectable non-small cell lung cancers. Following a traditional paradigm, antibody therapies were first studied in the adjuvant setting, after surgery and chemotherapy. Pivotal trials supported global approvals of the PD-L1/-1 antibodies atezolizumab and pembrolizumab in this setting. Exciting observations were made when checkpoint inhibitors were moved to the preoperative window. Several signal-finding studies explored a limited number of cycles prior to surgery and reproducibly reported complete or major histopathologic responses. So far, six published phase III trials have demonstrated the superiority of combining the PD-1/-L1 antibodies nivolumab, pembrolizumab, durvalumab, tislelizumab, or toripalimab with 3 to 4 courses of preoperative platinum-based chemotherapy over preoperative chemotherapy alone in terms of response rates and survival endpoints. Those patients achieving complete or major histopathologic responses experienced particularly favorable long-term outcomes. It is yet unclear whether there is true synergism between immunotherapy and chemotherapy and whether outcomes are further improved by adding postoperative checkpoint inhibition. Although these pivotal trials qualify neoadjuvant chemoimmunotherapy as another option in curative lung cancer treatment, there is hope that the chemotherapy backbone will be ultimately replaced by rationally selected and targeted combination partners. In this work, the current status and future avenues of neoadjuvant combination immunotherapies in patients with non-small cell lung cancer are reviewed.

Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management.

Experimental design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168-246], within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims.

Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P < 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P < 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P < 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P < 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations.

Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Purpose: The long-term effect of adipose-derived mesenchymal stromal cells (ASC) on restoring radiation-induced salivary gland hypofunction in patients with previous head and neck cancer has not been validated in larger settings.

Patients and methods: The study was a 12-month follow-up of a randomized trial, including patients with hyposalivation. Patients were randomized to receive allogeneic ASC or placebo in the submandibular glands. The primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module, and the xerostomia questionnaire), and safety.

Results: Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASC did not increase UWS compared with placebo: Increase in UWS was 0.02 mL/minute [95% confidence interval (CI), 0.01-0.04] in the ASC group and 0.02 mL/minute (95% CI, 0-0.03) in the placebo group (P = 0.56). ASC reduced the symptom burden for dry mouth with -10.07 units (95% CI, -13.39 to -6.75) compared with -4.15 units (95% CI, -7.46 to -0.84) in the placebo group (P = 0.01). Compared with placebo, ASC did not improve sticky saliva (-9.27 vs. -4.55 units; P = 0.13), swallowing (-4.50 vs. 3.49 units; P = 0.5), or xerostomia (-3.12 vs. -2.74 units; P = 0.82). Treatment was safe and associated with a transient immune response.

Conclusions: Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASC and placebo increased UWS, but ASC did not prove superior to placebo in restoring salivary gland function, based on the salivary flow rate.

Background: Anti-PD-(L)1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus (HPV)-associated malignancies. VEGF signaling causes intratumoral immune evasion and immune suppression. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.

Patients and methods: For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST v1.1). The primary endpoint was best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pretreatment/on-treatment biopsies) using a log-rank test.

Results: Among 20 participants, the overall response rate was 11% (95% confidence interval (CI): 1.2-32). Median PFS and OS were 4.1 months (95% CI: 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in interferon gamma (P=.03) and inflammatory response (P =.02) gene expression signatures with prolonged PFS, as did rises in CD3+CD8+PD1+ (P=.02) cells and decreases in CD3+FoxP3+ cells (P=.04) from 10 paired biopsies with multiplex immunoflorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter OS (HR 6.3, 95% CI 1.2-32; P=.01).

Conclusions: Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 monotherapy for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.

Background: Germline alterations in homologous recombination repair (gHRR) genes impact the pathogenesis, treatment options, and survival of cancer patients. However, distinct gHRR gene alterations may differentially impact treatment response and oncogenic signaling. Here we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities.

Methods: We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants (gBRCA1, gBRCA2, gPALB2, gATM, gCHEK2) were analyzed. Hazard ratios were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis was used to compare transcriptomic profiles.

Results: Somatic TP53 mutations were depleted in gATM carriers (p<0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with gBRCA1/2 mutations were associated with improved survival in ovarian cancer patients, and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (p<0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (p<0.001). Finally, using gene-dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function.

Conclusion: gATM-associated cancers appear to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.

Purpose: The phase 3 NATALEE trial reported a statistically significant invasive disease-free survival benefit with ribociclib plus nonsteroidal aromatase inhibitor (NSAI) versus an NSAI alone in stage II/III hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC). Here we report health-related quality of life (HRQOL) data from NATALEE.

Patients and methods: Patients were randomized to receive ribociclib plus NSAI or NSAI alone. Patient-reported outcome scores (EORTC QLQ-C30 global health status and physical, social, and emotional functioning domains; EORTC QLQ-BR23 breast-symptoms scale; health on a visual analog scale of EQ-5D-5L; and the Hospital Anxiety and Depression Scale) were assessed. The prespecified primary HRQOL endpoint was physical functioning. Mean scores and time-categorical and prespecified linear-time repeated-measure models were used to evaluate HRQOL changes during treatment.

Results: HRQOL was evaluated in all patients in the ribociclib plus NSAI (n = 2549) and NSAI alone (n = 2552) arms. Compliance was high in both arms (≈93%-97%). Mean scores did not differ meaningfully from baseline for any analyzed domain. Likewise, neither a meaningful change from baseline (in either treatment arm) nor a difference between arms was observed during treatment in the time-categorical, model-adjusted mean scores for any HRQOL domains-using published thresholds for interpreting longitudinal and between-group differences, with all values being within 0.5 SD of their baseline values. Linear-time regression analysis confirmed these findings.

Conclusions: These analyses of NATALEE show that adding adjuvant ribociclib to an NSAI does not negatively impact HRQOL in patients with HR+/HER2- EBC.