Local Immunotherapy of Cancer

Innovative Approaches to Harnessing Tumor-Specific Immune Responses

Vivek Murthy; Janna Minehart; Daniel H. Sterman

Disclosures

J Natl Cancer Inst. 2017;109(12) 

In This Article

Abstract and Introduction

Abstract

Modern cancer immunotherapies represent a major shift in paradigm with respect to how we understand innate and adaptive responses to malignancy. Successful tumors co-opt normal immunosurveillance mechanisms by potent interactions between the tumor and local draining lymph nodes. Tumor cells mediate a complex and dynamic immunoediting procedure that results in increased vascular efflux into the draining lymphatics, an immunosuppressive microenvironment rich in regulatory T-lymphocytes, dysfunctional antigen presentation, and downregulation of normal effector lymphocyte responses. Our current approach to reversing this process for antitumor effect involves mainly systemic administration of immunotherapeutic agents, many of which have become standard of care in the management of a variety of cancers. Despite this, we are still learning how best to administer these drugs alone and in combination to maximize efficacy while minimizing adverse events. Increasing evidence suggests that comparable efficacy may be achieved by local administration of immunotherapies in the tumor or tumor-draining lymph nodes with substantially lower doses and better tolerability, even with combination therapy. Herein, we review the literature on intratumoral and intranodal immunotherapies in preclinical models and early-phase studies, with particular emphasis on approaches potentially suitable for translation to larger-scale clinical trials.

Introduction

Modern cancer immunology traces its roots to the 1950s, when Burnet and Thomas proposed the theory of immune surveillance;[1] however, immunotherapy did not gain traction until the 1990s, when tumor-associated antigens (TAAs)[2–5] and peripheral immune tolerance due to lack of costimulation were demonstrated.[6–9] Immunotherapies have since become mainstream treatments of several cancers; however, we are still learning how to balance their efficacy against their unique adverse effects. Clinically significant morbidity and mortality have resulted from the systemic immune activation induced by current immunotherapies.[10–17] In light of increasing evidence of potential systemic immunogenicity of peritumoral immunomodulation, local therapies are being explored that target the tumor microenvironment and the center of immune education, the tumor-draining lymph node (TDLN).

Successful tumors undergo immune editing, whereby immunogenic cells are destroyed and only those able to evade recognition remain.[18,19] In addition to TAA downregulation, immune escape entails modification of the tumor microenvironment and the immune milieu through a wide range of mechanisms, including adaptations of tumors themselves. Central to this process is the TDLN, where antigen-presenting cells (APCs) and effector cells integrate complex signaling networks to generate the net immune response.[20] We will briefly review the role of the tumor environment and the TDLN in mediating antitumor immune responses, as well as provide a comprehensive overview of preclinical and clinical experience with local (tumor- and lymph node–directed) cancer immunotherapies.

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