Targeting the Undruggable

Immunotherapy Meets Personalized Oncology in the Genomic Era

S. D. Martin; G. Coukos; R. A. Holt; B. H. Nelson

Disclosures

Ann Oncol. 2015;26(12):2367-2374. 

In This Article

Abstract and Introduction

Abstract

Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology.

Introduction

We have entered an era in which personalized cancer interventions based on genomic data have great potential to improve patient outcomes. Proteins bearing somatic mutations represent ideal therapeutic targets, as they are often expressed exclusively by cancer cells. Recognizing this, many cancer centers are implementing personalized oncology programs that aim to use genomic approaches to identify optimal targeted therapies for individual patients. While this is an exciting and rational approach, it suffers from a major limitation: many cancer mutations are not easily 'druggable' by current pharmaceutical agents. T-cell-activating therapies are attractive alternatives, as in theory, T cells can recognize immunogenic mutations in any expressed protein, irrespective of the protein's biochemical function or subcellular location. Moreover, immunotherapies such as checkpoint blockade and adoptive T-cell therapy are yielding remarkable successes in the clinic. Intriguingly, genomic studies are revealing that mutated proteins are often the main target antigens underlying these successes.[1,2] On the basis of such findings, we discuss the rationale and evidence for including mutation-targeted immunotherapeutic approaches in personalized oncology programs.

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