Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions

ABSTRACT

Introduction

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a highly personalized type of cancer immunotherapy. TIL-based ACT exploits naturally occurring TILs, derived from the patients’ tumor. This treatment has shown consistent clinical responses in melanoma, and recent results point toward a potential use in multiple cancer diagnoses. However, several limitations have restricted the clinical development and adaptation of TIL-based ACT.

Areas covered

In this review, we present the principles of TIL-based ACT and discuss the most significant limitations for therapeutic efficacy and its widespread application. The topics of therapeutic resistance (both innate and acquired), treatment-related toxicity, and the novel research topic of metabolic barriers in the tumor microenvironment (TME) are covered.

Expert opinion

There are many ongoing areas of research focusing on improving clinical efficacy and optimizing TIL-based ACT. Many strategies have shown a great potential, particularly strategies advancing TIL efficacy (such as increasing and harnessing ex vivo the sub-population of tumor-reactive TILs) and manufacturing processes. Novel approaches can help overcome current limitations and potentially result in TIL-based ACT entering the mainstream of cancer therapy across tumor types.

KEYWORDS:

• Adoptive cell therapy
• cellular immunotherapy
• cell therapy
• resistance to immunotherapy
• tumor-infiltrating lymphocytes
• TILs

Declaration of interest

M Donia has given honoraria lectures Roche, Novartis, Bristol Meyers Squibb, Merck-Sharp-Dome, and Astra Zeneca Genzyme and has acted in an advisory role for Achilles Therapeutics. IM Svane has received an Adaptimmune Institutional Research Grant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article Highlights

• Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a highly personalized type of cancer immunotherapy. It has shown impressive clinical results and has gained interest because of its ability to induce long-lasting complete responses even in otherwise treatment-refractory patients.

• Manufacturing and administration of TILs for adoptive transfer requires three distinct phases: (i) isolation of TILs from fresh tumor tissue; (ii) ex vivo expansion of TILs in specialized Good Manufacturing Practice (GMP) facilities; and (iii) patient hospitalization, and infusion of autologous TILs to fight cancer.

• Despite impressive clinical results in some cancers, many patients do not respond to TIL-based ACT (innate resistance) or relapse after an initial response (acquired resistance), highlighting the need to better understand the mechanisms of therapy resistance.

• TIL-based ACT requires highly specialized GMP production facilities and is associated with severe treatment-related toxicity due to treatment with lymphodepleting chemotherapy before TIL infusion and subsequent high-dose interleukin-2. Together, these factors have been significant limitations in the widespread application of TILbased ACT.

• Dysfunctional T cell metabolism in the tumor microenvironment has not been thoroughly studied in TIL-based ACT, although it represents a potential challenge that could limit treatment efficacy

• The ex vivo expansion protocol provides a unique opportunity to modify and optimize the TIL infusion product. Potential strategies to increase the clinical efficacy include enrichment for tumor-reactive TILs, genetic engineering, or modulation of T cell metabolism.

Additional information

Funding

The paper was not funded.