Adoptive transfer with high-affinity TCR to treat human solid tumors: how to improve the feasibility?

Abstract

The adoptive transfer of tumor antigen-specific T cells recently achieved clinical efficacy for a fraction of melanoma patients refractory to other therapies. Unfortunately, the application of this strategy to the remaining melanoma and most other cancer patients is hampered by the difficulty to generate high-affinity tumor-reactive T cells. Two strategies are currently developed to extend the feasibility of this therapeutic approach: clinical grade tool production for MHC-peptide multimer-driven sorting of antigen-specific T cells from the endogenous peripheral T cell repertoire and de novo engineering of the missing repertoire by genetic transfer of cloned specific T cell receptor (TCR) into T cells. The expected multiplication of adoptive transfer treatments, by these strategies, and their careful evaluation should enable the cure of a number of otherwise compromised cancer patients and to gain insight into the characteristics of transferred T cells best fitted to eradicate tumor cells, in terms of antigen specificities, phenotype, and functions. In particular, identification of tumor-rejection antigens by this approach would improve the design and efficacy of all immunotherapeutic approaches.

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

“…Finally, cytokine cocktails and CD3 stimulation are used for expansion of the antigen-specific T cell population and subsequent reinfusion to the subject. 58,64 Expansion of antigen-specific T cells from the periphery has drawbacks that will hinder entry into mainstream cancer care. Firstly, paucity of antigenspecific T cells in the peripheral pool makes this method analogous to "finding a needle in a haystack."…”

Recent successes of cancer immunotherapy: a new dimension in personalized medicine?

“…Current cell transfer therapy approaches using autologous cells genetically engineered to express conventional or chimeric T cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma, and refractory lymphoma. Adoptive cell transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans and has evolved towards the administration of "young TILs" [1,2].Recently, the US Food and Drug Administration approved two novel immunotherapy agents, one based on a cancer vaccine (Sipuleucel-T, Dendreon) in patients with indolent hormone refractory prostate cancer and the other one based on targeting a pivotal T cell inhibitory receptor (anti-CTLA4 mAb, ipilimumab/Yervoy, BMS) in metastatic melanoma patients, which provide a survival benefit in two phase III clinical trials [3,4].These encouraging clinical results will be followed by many expected breakthroughs, according to the current evaluations worldwide. These include:…”

“…Current cell transfer therapy approaches using autologous cells genetically engineered to express conventional or chimeric T cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma, and refractory lymphoma. Adoptive cell transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans and has evolved towards the administration of "young TILs" [1,2].…”