The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Reviews co-Section Editor Dr. Sandra Demaria.
“Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy” by Dhan Chand et al
Cancer Discov. (2024)
Abstract: Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.
Why this matters: This article shows that a next-generation anti-CTLA-4 antibody engineered for enhanced FcγR affinity has clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Mechanistically, this antibody engages activating FcγR irrespective of FcγRIIIA genotype to reduce intratumoral Tregs. In addition, FcγR engagement on antigen presenting cells promotes their activation to improve their cross-presenting function. Together, these effects lead to optimal anti-tumor T cell activation. FcγRIIA and FcγRIIIA expression in the tumor is a candidate response biomarker. Overall, these results demonstrate that by refining the design of agents that target CTLA-4, it is possible to greatly improve their clinical efficacy, opening new therapeutic possibilities to extend the benefits of anti-CTLA-4 to more patients.
“Tumor-Infiltrating Lymphocytes in Patients with Stage I Triple-Negative Breast Cancer Untreated with Chemotherapy” by Veerle C. M. Geurts et al
JAMA Oncol. (2024)
Abstract:
Importance – The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking.
Objective – To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs.
Design, setting, and participants – This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023.
Main outcomes and measures – The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients.
Results – Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater.
Conclusions and relevance – Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.
Why this matters: In this article, the authors evaluated stromal tumor infiltrating lymphocytes (sTIL) in 1,041 patients with stage I triple negative breast cancer (TNBC) who had received neither neoadjuvant nor adjuvant chemotherapy. TILs were evaluated on H&E-stained slides using the guidelines established by the International Immuno-Oncology Biomarker Working Group. In the overall cohort, sTIL levels of at least 30% were associated with better breast cancer-specific survival (BCSS) compared with sTIL levels less than 30%. Notably, sTIL levels >50% in patients with pT1c tumors were associated with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater. Overall, the excellent 10-year BCSS outcomes of patients with stage I TNBC in the absence of neoadjuvant and adjuvant chemotherapy suggests that there is a subset of TNBC patients who do not benefit from chemotherapy and supports the importance of evaluating biomarkers of spontaneous anti-tumor immune response, such as sTIL, in prospective clinical trials to guide treatment decisions.
“Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy” by Emmanuel C. Patin et al
Nat Commun. (2024)
Abstract: The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.