Developing an Effective Breast Cancer Vaccine

Hatem Soliman, MD

Disclosures

Cancer Control. 2010;17(3):183-190. 

In This Article

Overcoming Tumor-related Immunosuppression

To allow tumor vaccines to deliver greater clinical benefits, especially in the metastatic setting, overcoming tumor-related immunosuppression is of paramount importance. Stimulated effector T cells may be appropriately primed to attack a TAA outside of the tumor microenvironment, but the tumor often renders these infiltrating cells inert once they arrive to attack the malignant cells.[41,42] Developing strategies to overcome these immunosuppressive mechanisms and combining them with vaccines may allow these stimulated effector T cells to attack malignant cells with greater efficiency.

Alteration of amino acid metabolism appears to be one of the important methods by which tumors induce immunosuppression both systemically and in the tumor microenvironment. One such area of active clinical investigation is the effect of tryptophan metabolism through overexpression of the enzyme indoleamine 2,3-dioxygenase (IDO) by tumors. Certain events in tumor development, such as mutations in the tumor repressor Bin1, lead to IDO overexpression when tumor cells are exposed to cytokines such as interferon gamma.[43] Increased IDO activity within the tumor microenvironment and draining lymph nodes causes local tryptophan depletion and production of catabolites such as kynurenine, which is toxic to infiltrating effector T cells and causes them to become anergic and die.[44–46] Also, naive T cells exposed to IDO expressing immature DCs become T regulatory cells that promote systemic anergy toward TAAs. The phase I solid tumor trial for a novel IDO inhibitor, 1-methyl-D-tryptophan (1-MT) is ongoing. However, data have shown that IDO inhibition can augment the response to DC vaccines in mice and synergize with chemotherapy agents such as taxanes, anthracyclines, and cyclophosphamide in regressing mouse MMTV-Neu breast tumors.[43] Current trials are combining 1-MT with a DC-based p53 vaccine and also with taxane chemotherapy to test these combinations in patients with metastatic breast cancer.

A similar enzyme called arginase exerts similar immunosuppressive effects through a breakdown of L-arginine to ornithine. This process promotes tumor growth and causes decreased effector T-cell activity, as evidenced by downregulation of CD3-zeta expression.[47,48] Agents that block arginase activity, such as 2(S)-amino-6-boronohexanoic acid, are currently in the early development stage for various conditions (eg, pulmonary arterial hypertension) and as cancer immunotherapy agents.[49]

The blockade of inhibitory signals that help to regulate the immune response has also been the subject of much research in various malignancies. CTLA-4 has been targeted using monoclonal antibodies such as ipilimumab and tremelimumab to block its inhibitory signal toward effector T cells. This approach has not been extensively clinically evaluated in breast cancer, but preclinical murine models suggest synergy with radiation.[50,51] B7-H1 is another potential inhibitory signal expressed by APCs infiltrating high-risk breast cancer types such as high Ki-67 and triple-negative subtypes. This signal binds to programmed death-1 (PD-1) on the surface of tumor-infiltrating lymphocytes, causing them to become anergic and undergo apoptosis.[52,53] Blockade of PD-1 using monoclonal antibodies currently in clinical development may allow tumor infiltrating lymphocytes to more efficiently kill tumor cells when stimulated with an appropriate target.

A comprehensive review of the various other immunosuppressive pathways involved is beyond the scope of this article. The main point is that pairing cancer vaccines with these immunomodulating agents will probably be required in order to improve the modest clinical efficacy observed so far in immunotherapy trials. Successfully testing these combinations can be challenging for several reasons. At a 2007 National Cancer Institute workshop on immunotherapy, the number of possible different combinations of cancer vaccines, adjuvants, and CTEP immunomodulating agents was calculated to be over 2,000.[54,55] Finding the combination that yields the maximal efficacy in a given disease is a daunting task. Another challenge will be determining which immunomodulators can be combined with vaccines without resulting in excessive toxicity from auto immune events such as severe colitis. Finally, overcoming the myriad of regulatory/intellectual property hurdles involved with combining multiple investigatory agents is not a trivial task. A concerted collaborative effort by the NCI, pharmaceutical companies, and regulators is required to prioritize combination immunotherapy strategies and facilitate their development.

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