Abstract
Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. Clinical translation has failed to recapitulate the promising results of pre-clinical studies although there have been some successes. In this review we explore some of the short-comings of cancer immunotherapy that have limited successful clinical translation. We will give special consideration to what we consider the most formidable hurdle to successful cancer immunotherapy: tumor-induced immune suppression and immune escape. We will discuss the need for antigen-specific immune responses for successful immunotherapy but also consider the need for antigen specificity as an Achilles heel of immunotherapy given tumor heterogeneity, immune editing, and antigen loss. Finally, we will discuss how combinatorial strategies may overcome some of the pitfalls of antigen specificity and highlight recent studies from our lab which suggest that the induction of antigen non-specific immune responses may also produce robust anti-tumor effects and bypass the need for antigen specificity.
Highlights
The allure of cancer immunotherapy as a potential magic bullet against cancer has intrigued researchers for over a century
Over the past decade there has been a renaissance in cancer immunotherapy with a renewed belief by many that harnessing the immune system may be a viable strategy for successfully treating metastatic disease
Numerous strategies are being explored including augmentation of antigenpresenting cells (APC) and immune effector cells, immunologic stimulants such as cytokines and pathogen associated molecular pattern (PAMP) receptor agonists, adoptive transfer of transgenic immune cells, antibodies and molecules such as anti-CTLA-4 antibody or transforming growth factor (TGF)-beta antisense aimed at reversing suppressive mechanisms, and numerous vaccines comprised of DNA, peptides, or autologous tumor cells [reviewed in Ref. [3, 4]]
Summary
The allure of cancer immunotherapy as a potential magic bullet against cancer has intrigued researchers for over a century. This may be one mechanism whereby antigen-specific therapies can overcome this shortcoming and it may be that only those patients who are able to overcome the outgrowth of tumor subclones which poorly express MUC-1 are able to produce a clinically meaningful response, this is not conclusively demonstrated.
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