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Noteable on Jan 28, 2024 11:18am
Anti-CTLA-4 vs Anti--PD-(L)1 Immune Checkpoint Inhibitors
Anti–CTLA-4 ICIs has been challenging because monotherapy has been comparatively less effective with higher rates of more serious immune-related adverse events (AEs) than the PD-1/PD-L1 class of inhibitors.
The challenges of targeting CTLA-4 are reflected in the long development arc for tremelimumab, a human IgG2 mAb. Preclinical work on the antibody began in the 1990s, followed by approximately 20 phase 1 and 2 trials in a range of tumor types. In 2008, investigators reported that tremelimumab failed to significantly improve median OS compared with the standard of care (temozolomide or dacarbazine) in patients with treatment-nave, unresectable stage IIIC or IV melanoma in a phase 3 trial (NCT00257205). In the final analysis, median OS was 12.6 months (95% CI, 10.8-14.3) for patients treated with tremelimumab vs 10.7 months (95% CI, 9.36-11.96) for participants who received chemotherapy (HR, 0.88; P = .127.
Some investigators theorized that the disappointing outcome of the study may have resulted from the enrollment of patients with a more favorable prognosis, leading to better-than-expected results in the control group, and in a potentially suboptimal dosing schedule. Additionally, standards for evaluating immune-related responses were not introduced until 2009 after most of the tremelimumab studies were designed.
During the next several years, however, combination regimens incorporating tremelimumab also failed to meet primary end points in pivotal studies in NSCLC, head and neck cancer, urothelial carcinoma, and small cell lung cancer.
The tide of clinical findings began turning in tremelimumab’s favor when investigators published the results of the phase 3 HIMALAYA trial (NCT03298451) in NEJM Evidence in June 2022. A total of 1171 patients with unresectable HCC and no prior systemic treatment were randomly assigned to receive tremelimumab plus durvalumab (n = 393), durvalumab alone (n = 389), or the angiogenesis inhibitor sorafenib (Nexavar) as monotherapy (n = 389).
Less than a month after approving the HCC indication, the FDA granted approval for tremelimumab in combination with durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC without sensitizing EGFR mutations or ALK alterations.
Botensilimab, a CTLA-4 inhibitor, is being developed through the FDA’s fast track program as combination therapy with balstilimab, an investigational PD-1 inhibitor, for patients with microsatellite-stable (MSS) metastatic CRC. The agent is an IgG1 antibody designed with an Fc-enhanced structure intended to improve T-cell priming, expansion, and memory while downregulating Tregs to amplify an immune response and decrease complement-mediated toxicity.
The combination of botensilimab plus balstilimab elicited an objective response rate (ORR) of 23% (95% CI, 14%-34%) in a cohort of 70 patients with MSS CRC who were treated during a multicohort first-inhuman trial (C-800-01; NCT03860272) in advanced cancers, according to findings reported at the 2023 ASCO Gastrointestinal Cancers Symposium in January. One complete response was reported (1%), 15 patients had partial responses (21%), and most (53%) had stable disease. The disease control rate was 76% (95% CI, 64%-85%). At the time of analysis, median OS had not been reached, and median PFS was 4.1 months (95% CI, 2.8-5.5). The 12-month OS rate was 63% (95% CI, 46%-76%).
This notwitstanding Oncolytics Biotech (ONCY) reovirus has a high propensity to replicate in KRAS mutant tumors which account for ~ 50% of MSS CRCs. Reovirus significantly enhanced the anti-tumor activity of anti-human PD-1 [nivolumab] treatment in MSS CRC cell lines ex vivo . Similarly, reovirus increased the activity of anti-mouse PD-1 treatment in the CT26 [MSS, KRAS Mut ], but not the MC38 [MSI, KRAS Wt ].
Activation of innate immune system and expression of PRRs and antigen presentation markers were observed under reovirus and anti-PD-1 treatment that additionally reduced immunosuppressive macrophages (i.e. Tregs). This led to an increase in T cell subsets, increase in effector T cell activation, and decrease in exhaustion markers specifically within CT26 microenvironment. Conclusion The current study systematically evaluates immune characteristics and immune microenvironment of CRC under reovirus/anti-PD-1 combination treatment that proves increased effectiveness among MSS compared to MSI CRCs.
One Sentence Summary Oncolytic reovirus alters innate and adaptive immune system and potentiates MSS type colorectal cancer to checkpoint inhibition therapy.
https://www.researchgate.net/publication/354366611_Reovirus_sensitizes_microsatellite_stable_colorectal_cancer_to_anti-PD-1_treatment_via_cross-talk_in_innate_and_adaptive_immune_systems
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Noteable on Jan 28, 2024 2:02pm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9814316/