Combinations ‘Likely the Way Forward’ for Breast Cancer Immunotherapy Research

Despite breast tumors’ lower mutational loads than lung cancers and melanoma-cancers in which immunotherapy have shown particular promise-breast cancers are nevertheless immunogenic, Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the 34th Annual Miami Breast Cancer Conference, held March 9–12 in Miami Beach, Florida.

Multiple clinical trials are now underway to evaluate immunotherapy strategies in breast cancer, Mittendorf noted.

Combination immunotherapy regimens are “likely the way forward” and appropriate combinatorial strategies will hinge importantly on disease stage, she said.

Cancer immunotherapies work by provoking attacks on tumor cells by patients’ immune systems. Examples include cancer vaccines, adoptive T-cell therapies such as chimeric antigen T cells, and immune checkpoint inhibiting monoclonal antibodies. Immune checkpoint blockade targets T-cell inhibitory signal molecules like programmed death (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and thereby “taking the brakes off the immune response,” Mittendorf said. That allows the patient’s tumor-targeting T cells to proliferate and attack tumor tissue.

Melanoma, adenocarcinoma, and squamous cell carcinoma of the lung have some of the highest mutational loads for human cancers, whereas breast tumors’ mutational loads trail those seen in gastric, esophageal, colorectal, head and neck, cervical, ovarian, brain, kidney, and pancreatic cancers, among others. That contributed to some early skepticism that breast cancer was a promising target for immunotherapies.

But breast tumors are now known to express several putative tumor-associated antigens (TAAs), such as those on which the human epidermal growth factor receptor 2 (HER2)-derived E75 peptide, GP2-peptide, and AE37-peptide cancer vaccines were based. Mittendorf’s team at MD Anderson Cancer Center has shown that 20% of triple-negative breast cancer tumors express PD-L1, for example.

While peptide vaccine monotherapies have been “largely ineffective” in metastatic disease, they tend to be quite safe and might play an important role improving the efficacy of other immunotherapy strategies, Mittendorf suggested. For example, combining cancer vaccines with immune checkpoint blockade agents might create mechanistic synergy, stimulating T-cell response and increasing TAA presentation.

Similarly, there are multiple mechanisms of synergy whereby combining vaccines and trastuzumab could similarly enhance combined immunotherapy regimens, Mittendorf said. “We have two trials underway to look at this,” she noted.

Such strategies augment T-cell infiltration of the tumor microenvironment and tumor tissue.

Cancer peptide vaccines are only one way to increase TAA presentation. One mechanism whereby chemotherapy and radiotherapy might help fight cancer is immunogenic cell death, with dying tumors releasing TAAs, for example. Early clinical study findings from 19 patients with early-stage breast cancer suggests that combining the CTLA-4-targeting immune checkpoint inhibitor ipilimumab with cryoablation (cryoimmunotherapy) might offer a similar therapeutic synergy, with tumor cryoablation releasing TAAs that the ipilimumab-stimulated immune system then recognizes and attacks in other tumors, Dr. Mittendorf noted.