Novel Combinations of Human Immunomodulatory mAbs Lacking Cardiotoxic Effects for Therapy of TNBC

SIMPLE SUMMARY: Immunotherapy has revolutionized the management of cancer by improving outcomes of triple-negative breast cancer (TNBC). Recently, programmed death-ligand 1 (PD-L1), was identified as a target for TNBC and several preclinical and clinical trials are currently focusing on combinatorial treatments of immunomodulatory mAbs with chemotherapy, radiotherapy, or other mAbs. Here, we tested in in vitro models novel combinations of immunomodulatory mAbs on TNBC cell lines and on cardiomyocytes, in comparison with the mAbs approved by FDA for cancer therapy, in order to identify at early stages the more potent anti-cancer combinations endowed with low or no cardiotoxic side effects. ABSTRACT: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by a higher mortality rate among breast cancer subtypes. Poly(ADP-ribose) polymerase (PARP) inhibitors are used in clinics to treat a subgroup of TNBC patients, but other targeted therapies are urgently needed. Programmed death-ligand 1 (PD-L1), involved in tumor immune escape, was recently identified as a target for TNBC; accordingly, the anti-PD-L1 monoclonal antibody (mAb), atezolizumab, has been approved by FDA in combination with Paclitaxel for the therapy of metastatic TNBC. Here, we tested novel combinations of fully human immunomodulatory mAbs, including anti-PD-L1 mAbs generated in our laboratory and atezolizumab, on TNBC and other tumor cell lines. We evaluated their anti-tumor efficacy when used as single agents or in combinatorial treatments with anti-CTLA-4 mAbs in in vitro co-cultures of hPBMCs with tumor cells, by measuring tumor cell lysis and IL-2 and IFNγ cytokines secretion by lymphocytes. In parallel, by using co-cultures of hPBMCs and cardiomyocytes, we analyzed the potential cardiotoxic adverse side effects of the same antibody treatments by measuring the cardiac cell lysis and the secretion of pro-inflammatory cytokines. We identified novel combinations of immunomodulatory mAbs endowed with more potent anti-cancer activity on TNBC and lower cardiotoxic side effects than the combination of atezolizumab and ipilimumab.