The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical Trials Monitor Section Editor, Dr. Leisha A. Emens.
“Decade-long leukemia remissions with persistence of CD4+ CAR T cells” by J Joseph Melenhorst et al
Some patients who received CAR T cell therapy nearly one decade ago when these modalities first entered the clinic are still experiencing ongoing remissions. Long-lasting CAR T cells that persisted in two patients with chronic lymphocytic leukemia (CLL) who were treated with CD19-specific CAR T cells in 2010 are described by J Joseph Melenhorst and colleagues. Both patients had detectable levels of CTL019 cells (the product that was eventually approved as tisagenlecleucel) at 9−10 years post-infusion, with little to no detection of CD19 B cells. Interestingly, the clonal dynamics of the CAR T cells in both patients varied considerably, with stabilization occurring later for one patient, and sporadic periods of clonal stability for the other. Single-cell sequencing analyses of T cells in one patient at 9.3 years post-infusion revealed very low clonal diversity in the CAR T cells compared to endogenous T cells, with three clonotypes making up over 90% of the CAR T cell populations. In both patients, early CD8+ or CD8-CD4-Helioshiγδ CAR T cell populations were eventually dominated by CD4+ T cells, which persisted long-term. These CD4+ CAR T cells were highly proliferative and had phenotypes consistent with cytotoxicity, including activation markers CD38 and HLA-DR, upregulation of genes associated with cytotoxicity including GZMK, GZMA, and PRF1, and antigen-driven production of activating cytokines interleukin (IL)-10 and IL-32.
Why this matters: Understanding of the phenotypes of CAR T cells that persist and allow for long-lasting remissions may help inform the development of future CAR T products to take advantage of these attributes.
“Prospective Cardiovascular Surveillance of Immune Checkpoint Inhibitor-Based Combination Therapy in Patients with Advanced Renal Cell Cancer: Data from the Phase III JAVELIN Renal 101 Trial” by Brian I Rini et al
Journal for Clinical Oncology, 2022
Brian I Rini et al describe the first prospective biomarker analysis for risk of major adverse cardiovascular events (MACE) with combination anti-PD-L1 and vascular endothelial growth factor receptor tyrosine kinase inhibitor treatment. The relative risk for MACE, including cardiac death, fatal stroke, and nonfatal events of myocardial infarction, congestive heart failure, myocarditis, arrhythmia, and stroke, was correlated with baseline cardiovascular risk factors for 873 patients who received either avelumab plus axitinib or sunitinib in the phase III JAVELIN Renal 101 study. Other than a trend toward association of dyslipidemia with MACE in the avelumab plus axitinib arm, there were no correlations between cardiovascular risk factors and MACE. Although MACE occurred roughly two-fold more frequently in the avelumab plus axitinib arm versus the sunitinib arm, the difference was not statistically significant. The rates of hypertension and LVEF decline were higher for avelumab plus axitinib compared to axitinib. However, neither hypertension nor LVEF decline were associated with MACE in either treatment arm. The only biomarker that was significantly associated with increased risk for MACE was abnormal baseline troponin T, specifically for patients receiving avelumab plus axitnib (relative risk for avelumab plus axitinib 3.31, 95% CI 1.19 to 9.22; relative risk for sunitinib 0.89, 95% CI 0.2 to 3.98).
Why this matters: This study reports the first prospective biomarker analysis for risk of adverse events with an immunotherapy combination regimen. Elevated baseline troponin T may inform a risk-benefit discussion and heightened adverse event monitoring for patients with RCC receiving combination avelumab plus axitinib.
“Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy” by Melody Smith et al
Nature Medicine, 2022
CAR T cell therapies have improved survival outcomes for many hematologic malignancies. A significant number of patients, however, have disease that is resistant or becomes refractory. Melody Smith and colleagues investigated the association of antibiotic use, the intestinal microbiome, and the fecal microbiome with response to CAR T cell therapy in patients with B cell malignancies. Retrospective analyses found that any antibiotic use within 4 weeks prior to administering CAR T cell therapy was associated with significantly reduced overall survival (OS). Specifically, the anaerobe-targeting antibiotics piperacillin/tazobactam, imipenem/cilastatin and meropenem (collectively, PIM)—commonly used to treat neutropenic fever—were associated with worse OS when compared to no antibiotic use and to use of non-PIM antibiotics. PIM antibiotics were also associated with an increased incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) specifically in patients with Non-Hodgkin lymphoma (NHL), but not in patients with acute lymphoblastic leukemia (ALL). Additionally, a higher pre-treatment alpha-diversity in the fecal microbiota was associated with an increased probability of a 100-day complete response (CR) to CAR T cell therapy. Taxonomic analysis of 16S ribosomal DNA sequence identified Clostridia microbes that were associated with day 100 CR to CAR T cell therapy, specifically, Ruminococcus, Bacteroides, and Faecalibacterium. No specific constituents of the fecal microbiota were associated with risk for toxicity.
Why this matters: This study underlines the importance of the microbiome for immunotherapy response, and suggests that practitioners should be judicious in the use of antibiotics in a patient being considered for CAR T cell therapy.
“Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma” by Hussein A Tawbi et al
New England Journal of Medicine, 2022
Dual checkpoint blockade with the LAG-3-blocking antibody relatlimab and the anti-PD-1 antibody nivolumab has demonstrated safety and efficacy for patients with advanced, previously-treated melanoma. The phase II/III RELATIVITY-047 trial, reported by Hussein A Tawbi et al, assessed the combination of nivolumab plus relatlimab in the frontline setting. A total of 714 patients with unresectable or metastatic melanoma were randomized to receive nivolumab plus relatlimab (n=355) or nivolumab alone (n=359). The primary endpoint was progression-free survival (PFS), as assessed by a blinded independent central review according to RECIST v1.1. With a median follow up of 13.2 months, median PFS was significantly longer for the combination of nivolumab and relatlimab compared to nivolumab monotherapy (10.1 months vs 4.6 months; HR 0.75 [95% CI 0.62 to 0.92], p= 0.006). In prespecified exploratory subgroup analyses, PFS favored nivolumab plus relatlimab regardless of disease stage, tumor burden, LDH level, PD-L1 expression status, and BRAF mutation status. Notably, neither LAG-3 nor PD-L1 expression predicted benefit from nivolumab combined with relatlimab relative to nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients receiving nivolumab plus relatlimab and 9.7% of patients in the nivolumab arm. Three treatment-related related deaths (0.8%) occurred in the nivolumab plus relatlimab arm and two treatment-related deaths (0.6%) in the nivolumab arm.
Why this matters: RELATIVITY-047 provided the basis for FDA approval of nivoulmab plus relatlimab for the first-line treatment of metastatic melanoma. Relatlimab is the first new checkpoint inhibitor to gain regulatory approval since 2014 and is currently being evaluated for the treatment of several additional solid tumors.
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