Towards Curative Cancer Immunotherapy: Overcoming Posttherapy Tumor Escape

[D.ap]

Abstract


The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.

Counterregulation Mechanisms That May Lead to Posttherapy Tumor Escape

It is not uncommon both in clinical studies and animal models that some cancer immunotherapies can induce measurable immune responses, but these responses did not translate into durable beneficial outcomes, suggesting the occurrence of tumor immune escape. Many factors may contribute to tumor escape under the immune pressure imposed by therapies, including immunogenicity alterations (downregulation of MHC expression, loss of antigen) in tumor cells in response to therapy, amplification of immunosuppressive cells (Tregs, MDSCs), and induction of immune checkpoint molecules in effector T cells (CTLA-4, PD-1). There is emerging evidence that certain components of the therapy regimen, and/or some immune products induced by therapy, may induce or exacerbate some of these tumor escape pathways. In this section, we discuss the possible mechanisms by which tumors antagonize and subvert robust immune responses in the posttherapy setting, thereby promoting tumor escape



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386616/