The Promise of B-Cell Epitope Immunotherapies: Combinatorial HER-2, PD-1, PD-L1 & CTLA-4 Checkpoint Inhibitor Peptide Vaccines

In light of the numerous US FDA-approved humanized monoclonal antibodies (mAbs) for cancer immunotherapy, it is surprising that the advancement of B-cell epitope vaccines designed to elicit a natural humoral polyclonal antibody response has not gained traction in the immune-oncology landscape. Passive immunotherapy with humanized mAbs (Trastuzumab [Herceptin] Pertuzumab [Perjeta] has provided clinical benefit to breast cancer patients, albeit with significant shortcomings including toxicity problems and resistance, high costs, sophisticated therapeutic regimen and long half-life. The role of B-cell humoral immunity in cancer is under appreciated and under-developed. Thus, we have advanced the idea of active immunotherapy with specially designed chimeric B-cell epitope peptides incorporating a ‘promiscuous’ T-cell epitope that elicits a polyclonal antibody response, which provides safe, cost–effective therapeutic advantage over mAbs. We have developed two chimeric peptides comprising an herceptin-like and Perjeta-like conformational B-cell epitope vaccines and have translated our HER-2 vaccines in two Phase I/Ib clinical trials (NCT01376505; IND #14633) in breast and colon cancers overexpressing HER-2, and we have demonstrated excellent safety and anticancer immunity. This trial is being transferred from OSU to IUSCCC.

Cancer immunotherapy with checkpoint inhibitors has also resulted in impressive clinical results by restoring anti-tumor immunity and affording durable responses in several different cancer indications. Blockade of checkpoint receptors with monoclonal antibodies against cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4, ipilimumab) and program cell death protein 1 (anti PD-1, nivolumab) and its ligand (anti PD-L1, atezolizumab) has shown great clinical success in several cancer subtypes, yielding unprecedented responses. Despite this success, only a fraction of patients show a durable and complete response to monoclonal antibody drugs exhibiting a wide spectrum of immune-related adverse events, including the rapid development of resistance, poor tissue penetration, off-target effects, high treatment costs and high toxicity rates. Combinations of ICI have been advanced to resolve these problems, however with increased incidence of adverse events and autoimmunity.

We introduced the development of novel chimeric vaccines PD-1(PD1-Vaxx), PD-L1 (PDL1-Vaxx) and CTLA-4 (CTLA-4-Vaxx) B-cell peptide epitope vaccines and in preclinical studies in syngeneic BALB/c -CT26 and C57BL6/J-MC38 colon carcinoma mouse models. These studies support our effort to find a cure for colorectal cancers (CRC) which is set to take the most lives of people under 50 by 2030. In the USA, 5-year survival is only 12.5%, reflecting a clear unmet need for more effective treatments for patients with metastatic CRC (mCRC).

We have conducted in vivo efficacy combination studies: (i) PD1-Vaxx, (ii) PDL1-Vaxx and (iii) CTLA-4-Vaxx in syngeneic BALB/c 4T1 carcinoma mouse models to identify the best combination vaccine candidate as demonstrated by inhibition of tumor growth, prolonged survival rate and correlative in-vitro studies. Triple Negative Breast Cancer (TNBC) is an aggressive and deadly type of cancer that accounts for 15% of breast cancer cases diagnosed in the USA. It more frequently afflicts young women and those of African and Hispanic ancestry. In this presentation, I will review and discuss our approaches and strategies that focus on B-cell epitope cancer vaccines and combination onco-immuno strategies for CRC and TNBC.