Chemotherapy and tumor immunity: an unexpected collaboration

Abstract

Chemotherapy directly targets the transformed tumor cell, and has long been a key component of therapy for most early and advanced cancers. However, its utility is ultimately limited by unavoidable toxicity to normal tissues, and by drug resistance pathways deeply embedded within the biology of the tumor cell itself. These limitations strongly argue for innovative strategies to treat and manage cancer. Engaging the power of the patient's own immune system is a highly attractive way to complement the activity of standard cancer treatment. Tumor vaccines offer the potential for preventing cancer in those at high risk for disease development, preventing relapse in those diagnosed with early cancer, and treating advanced disease. Notably, the barriers to tumor vaccine efficacy are distinct from the limitations of combination chemotherapy. The ability of vaccines to induce a response robust enough to mediate tumor rejection is limited by the extent of disease burden, the suppressive effect of the local tumor micronenvironment, and multiple layers of systemic immune tolerance established to keep the immune response turned off. Chemotherapy can be used with tumor vaccines in unexpected ways, breaking down these barriers and unleashing the full potential of the antitumor immune response. KeywordsTRAIL; CEA; rVV; PSA; GM-CSF; CTL; TLR; LPS; Tumor Immunity; Chemotherapy; Cancer Vaccines; Immune Tolerance; Review INTRODUCTIONCurrent cancer therapies are limited either by local modes of action that fail to eradicate distant disease, or by inherent drug resistance integral to the biology of the transformed tumor cell. Many years of refining traditional modes of therapy have maximized their efficacy, but further therapeutic gains of significance are unlikely. More recently, biologically targeted drugs that precisely interrupt signaling pathways indispensable for tumor growth and progression have produced substantial improvement. As examples, the use of Trastuzumab to treat HER-2/neu-overexpressing breast cancer (1) and Imatinib to manage chronic myelogenous leukemia (2) greatly improve patient outcomes. Despite their promise, even precisely targeted therapeutics will ultimately be limited by drug resistance, resulting in disease relapse. This limitation of therapies that target the tumor cell itself is a call for the development of cancer therapies that work in a fundamentally different way. Tumor vaccines can recruit the power of the patient's own immune system to actively seek out and destroy transformed tumor cells, and represent a potentially potent complement to standard cancer therapies. Immune-based therapy has a higher level target than the tumor cell itself, re-tooling the host-tumor interaction to induce host cells that favor tumor rejection. Additional unique features of immune-based therapy make it even more attractive. Tumor vaccines can potentially induce a durable antitumor effect by virtue of the immunologic memory response, even in the absence of continued therapy. This memory response also defines im...

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