The Sentinel


Saturday, November 14, 2020

SITC 2020 Scientific Highlights – Nov. 14, 2020

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 14, 2020, sessions of the 35th Anniversary Annual Meeting.

Method for personalized immunotherapy response prediction developed

Plasma-based proteomic profiling as a tool for predicting response to immunotherapy in melanoma patients

Michal Harel, PhD (Oncohost LTD), discussed a method for profiling patients with melanoma to predict response to immunotherapy. The group utilized proteomic profiling of plasma samples before treatment and early after initiation of anti-PD-(L)1 therapy to develop a predictive signature using machine learning. They also aimed to identify biological pathways that differed between responders and non-responders.

A 3-protein signature was developed and was able to distinguish responders from non-responders in the validation cohort with a sensitivity and specificity of 0.75 and 0.9, respectively. Using the signature, a personalized response prediction could be developed for individual patients. Further evaluation of biological pathways identified potential resistance mechanisms in non-responders, such as upregulation of inflammation, proliferation, metastasis and angiogenesis processes. Different pathways were upregulated in tumors that failed to respond to PD-(L)1 monotherapy compared to those also treated with anti-CTLA-4, indicating varying biological underpinnings for resistance. In a case study, the group discussed identification of a potential resistance-associated protein in a patient with melanoma, leading to recommendations for potential clinical trials targeting that resistance mechanism.

CD47 blockade may boost immune response to TNBC

An immune-competent tumor organoid platform to test novel immune checkpoint combinations targeting the receptor CD47 in triple negative breast cancer

Elizabeth Stirling, MS (Wake Forest School of Medicine), presented preclinical methods to investigate CD47-targeted therapies in triple negative breast cancer. The group utilized organoid tissue culture, murine models, and tissue analysis in their study. 

CD47 expression varied between primary and metastatic human TNBC tumors and was also higher in non-responding tumors than responders to PD-1 therapy. Given this, the group investigated CD47 blockade in murine models of TNBC and found that this therapy significantly decreased tumor growth. There was evidence for increased intratumoral CD8+ T cells and granzyme B expression in the tumor tissue after treatment. Treated tumors were also more sensitive to PD-L1 blockade. A 3D organoid model, which included co-incubation of tumor-specific cytotoxic T cells, was used to test CD47 therapy as well, and also revealed increased granzyme B and interferon gamma expression with treatment. The authors feel that the organoid model used in this study could be a valuable resource for future therapeutic studies.

p53-specific T cell therapy may be efficacious and widely-applicable

Adoptive T cell therapy targeting somatic p53 mutations

A p53-targeted adoptive T cell therapy was discussed by Peter Kim, PhD (National Cancer Institute). Given that p53 is the most commonly-mutated cancer driver gene, cell therapies targeting common p53 mutations may be widely-applicable.

The group found that 22% of screened patient TILs were responsive to mutant p53, which included 46 different TCRs. However, patients that were treated with autologous TILs largely did not respond to the therapy, with 2 PRs found in 12 patients. The infused TILs were found to have low frequencies of mutant p53-specific TILs, and had a high level of differentiation and exhaustion. The group hypothesized that genetic engineering of T cells may overcome these problems and thus treated a patient with breast cancer with adoptive transfer of autologous PBLs that had been retrovirally transduced with an anti-p53 R175H TCR. The patient’s tumors shrunk by 55% after this treatment, despite having progressed on 10 other therapies. The engineered cells were found to be more persistent and have greater p53 reactivity than naturally-occurring TIL, making this strategy a promising one for future wide-scale immunotherapy.

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