Anti-PD-1 therapy, evaluating tumor-specific MHC-II expression to predict clinical benefits

Identifying HER-2 negative breast cancer patients who may have the best response to immunotherapy in addition to neoadjuvant chemotherapy could soon become a reality: a retrospective study  published in Clinical Cancer Research indicates that an evaluation of the class II major histocompatibility complex (MHC-II) tumor-specific expression could be a novel biomarker to identify patients where immunotherapy added to neoadjuvant chemotherapy could be of clinical advantage.

Immunotherapies targeting PD-1 / L-1 provides clinical benefit in a number of patients with breast cancer, but so far there are no biomarkers able to predict the response: a biomarker would be relevant, since  many patients treated with neoadjuvant chemotherapy achieve pathologic complete response without immunotherapy, which is not without toxicity. Identifying who could benefit most from the combination therapy is therefore important, so Kim Blenman from Yale University, Justin Balko from Vanderbilt University and their colleagues have tried to understand what could be used as a biomarker by analyzing tissues taken from patients with primary breast cancers not treated with immunotherapy, with triple negative tumors treated with neoadjuvant chemotherapy and durvalumab, or with HER-2 negative tumors treated with neoadjuvant chemotherapy with or without pembrolizumab.

The data show that tumor-specific expression of MHC-II is associated with improved survival in the latter patients with high-risk, HER-2 negative tumors when anti-PD immunotherapy is added to neoadjuvant chemotherapy. 1. The authors explain: «The factors driving tumor cell-specific MHC-II expression are not entirely clear, although it’s expression can be driven by inflammatory signals, such as interferons in the tumor microenvironment; however, they are not only an interferon-responsive marker, because many cell lines constitutively express MHC-II without interferon stimulation a wide variety of tumor cell lines that will not upregulate MHC-II with interferon treatment. The expression of tumor-specific MHC-II is an important object of study and our data show that it can be an independent specific predictor of response and event free-survival to the addition of an anti-PD-1/PD-L1 to standard neoadjuvant chemotherapy».

The researchers stress that data must be interpreted with caution due to the small sample study size (less than 100 cases per arm) and also due to the retrospective nature of the analyses. «Nonetheless, this is the first study to evaluate and demonstrate the predictive capacity of tumor MHC-II for immunotherapy benefit in breast cancer patients», the authors say. «The utility of tumor-specific MHC-II was verified by two independent approaches and in two different patient populations, with different anti-PD-1 and anti-PD-L1 antibodies: these data therefore suggest that tumor-specific MHC-II may be a potential biomarker which can be measured easily by tissue analyses, including standard immunohistochemistry, that should be included in correlative analyses in future breast cancer immunotherapy Phase II and III trials».