The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Clinical/Translational Cancer Immunotherapy Section Co-Editor, James L. Gulley, MD, PhD, FACP.
Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma by Jennifer Brudno et al.
Neurologic toxicity was the most clinically significant class of toxicity in several of the trials leading up to the approval of the chimeric antigen receptor (CAR) T cell therapy axicabtagene ciloleucel, with as many as 50% of patients experiencing severe (grade 3 or 4) neurologic adverse events. Jennifer Brudno and colleagues constructed a CAR that, when transduced into T cells and infused into patients, caused significantly less neurotoxicity as the approved therapy while maintaining comparable anti-lymphoma activity in a first-in-human, phase 1 trial. In the trial, which included 20 patients with B cell lymphoma, the ORR was 70% and only 5% (1/20) of patients experienced grade 3 or 4 neurologic toxicity. Grade 2 or higher neurologic toxicity was observed in 20% (4/20) of patients, substantially lower than the 77% rate reported in prior axicabtagene ciloleucel trials. Containing an identical CD28 co-stimulatory domain as the CAR that was eventually approved as axicabtagene ciloleucel, FMC63-28Z, the new CAR, Hu19CD828Z, consisted of a fully human (as opposed to murine) anti-CD19 scFv as well as a CD8alpha-derived transmembrane and hinge region (instead of CD28). Peak blood levels of T cells transduced with both CARs were equivalent, and the blood levels of Hu19CD828Z CAR T cells one month after infusion were higher than those for FMC63-28Z CAR T cells. Systematic functional comparisons between T cells transduced with Hu12CD828Z- and FMC63-28Z-based CAR constructs differing by only one component revealed that the hinge and transmembrane domains were key (but not sole) determinants of inflammatory cytokine production in vitro. The study demonstrates that clinically effective anti-CD19 CARs containing CD28 costimulatory domains are not always associated with high levels of toxicity—offering a potential strategy for improved design of future therapies.
Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer by Anders Etzerdot et al.
Tissue-associated macrophages (TAMs) have been well-characterized as key players in promoting tumor progression and metastasis, yet little is known about if and how different subsets of tissue-resident and infiltrating macrophages influence malignant processes in cancer. Using mouse models of metastatic ovarian cancer that recapitulate several features of visceral peritoneal metastases, Anders Etzerdot and colleagues defined a unique subset of tissue-resident macrophages that promote epithelial to mesenchymal transition (EMT) and metastatic spread. Characterization of TAMs in the omentum (the most frequent site for metastasis in high grade serous ovarian cancer) through single-cell RNAseq, flow cytometry and confocal imaging revealed four distinct clusters, defined by the expression of surface markers CD163 and Tim4 as well as localization in premetastatic niches. Lineage tracing experiments revealed that the specific subset of CD163+ Tim4+ TAMs were not derived from bone-marrow precursors, and at least a significant portion were of embryonic origin. The CD163+ Tim4+ macrophages expressed a unique transcriptional profile, characterized by positive regulation of JAK-STAT signaling. Depletion of CD163+ Tim4+ macrophages (both genetically and pharmacologically) significantly reduced ascites formation and metastases to the diaphragm. Furthermore, tumor cells isolated from CD163+ Tim4+ macrophage-depleted mice exhibited decreased expression of the positive regulators of EMT Stat3, Wnt5a and Mertk. The findings add new insight into heterogeneity of TAMs, implicating specific subsets of tissue-resident macrophages in establishing the pre-metastatic niche and potentially identifying new therapeutic targets.
Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab A Phase 2 Clinical Trial by Clara Kelly et al.
Few effective treatment options exist for sarcomas, and trials of immune checkpoint inhibitors to date have failed to demonstrate substantial improvements in objective response rates compared to standard-of-care chemotherapy. Reasoning that oncolytic virus immunotherapy combined with checkpoint inhibition could synergistically augment anti-cancer activity by increasing tumor-infiltrating lymphocyte (TIL) infiltration and PD-L1 expression, Clara Kelly et al. enrolled 20 patients with different subtypes of locally advanced or metastatic sarcoma in a single-institution, phase 2 study a combination regimen consisting of talimogene laherparepvec (T-VEC) and pembrolizumab. The ORR at 24 weeks was 30%, with one patient with cutaneous angiosarcoma experiencing a delayed response at 32weeks, making the best overall ORR 35% (95% CI, 15%-59%). The combination was well-tolerated, with one case of pneumonitis being the only grade 3 or higher immune-mediated adverse event. Immunohistochemical analysis of pre-and post-treatment biopsy samples from responding patients revealed a consistent pattern of clusters and nodular aggregates of CD3+/CD8+ TILs at the edges of tumors prior to treatment, and increased numbers of CD3+/CD8+ TILs overall in post-therapy samples—neither of which were observed in any samples from non-responsive patients. The results represent some of the highest ORRs reported in an unselected sarcoma study population evaluating combination immunotherapy, supporting further evaluation of T-VEC combined with pembrolizumab in specific sarcoma subtypes.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma by James Larkin et al.
Metastatic melanoma has historically been associated with very poor 5-year survival rates. The advent immunotherapy has significantly improved outcomes in metastatic melanoma and significant progression-free and overall survival benefits have been reported for patients treated with the combination of nivolumab and ipilimumab. In a new update from the CheckMate 067 trial, which compared combination nivolumumab and ipilimumab to single-agent therapy, James Larkin et al. report sustained long-term overall survival at 5 years in metastatic melanoma patients who received both the dual drug regimen and nivolumab alone, with no apparent loss in quality of life. At a minimum follow up of 60 months, the median overall survival was not yet reached in the nivolumab plus ipilimumab group, 36.9 months in the nivolumab group and 19.9 months in the ipilimumab group. Overall survival at 5 years was 52% for the dual regimen, 44% in the nivolumab group and 26% in patients receiving ipilimumab alone. Among patients with tumors with BRAF mutations overall survival at 5 years was 60% for the nivolumab plus ipilimumab group, 46% for the nivolumab group and 30% for the ipilimumab group, whereas among patients without BRAF mutations, the overall survival rates were 48%, 43% and 25%, respectively. No new safety signals nor previously unreported long-term toxic effects were observed.
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