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Introduction

Adoptive T cell therapy (ACT) is treatment with immune cells collected from a patient, then grown and manipulated in a laboratory and subsequently administered back to the patient. The aim is to induce a specific anti-tumour response, making ACT a highly personalized form of immunotherapy. ACT takes two main forms:

  • T cells that have natural anti-tumour reactivity, for example tumour-infiltrating lymphocyte (TIL) therapy.

  • T cells that are gene-modified to direct an anti-tumour response, for example chimeric antigen receptor therapy.

This chapter focuses on the use of lymphocytes that have natural anti-tumour reactivity, specifically TIL therapy.

Background

TILs are naturally occurring cells that have the ability to infiltrate tissue with the purpose of specifically recognizing malignant cells and eliminating them. They do so either by recognizing antigens shared by the patient and the malignant cells (self antigens)1 or by recognizing tumour-specific antigens (neoantigens), the latter being present due to somatic mutations of the malignant cells.2 TILs are generated as part of an adaptive immune response to the cancer when considered foreign by the immune system. In some cases, emerging tumours can develop means of avoiding elimination by the immune system, and clinically detectable cancer disease will develop.3 ACT with TILs exploits the fact that the adaptive immune system has already generated specific TILs against the cancer that can potentially recognize and eliminate the cancer cells but are being prevented from doing so. There may be several reasons why TILs are not able to eliminate malignant cells; some of these can be diminished or bypassed through conditioning and stimulating treatment in relation to ACT with TILs. This, and the historical development of ACT with TILs, will be elaborated upon in this chapter.

Recent developments

Development of TIL therapy

In the 1980s, Rosenberg et al.4 discovered in a murine model that TILs in combination with the T cell growth factor interleukin (IL)-2 were superior to lymphokine-activated killer cells in killing cancer cells and seemed to retain specificity for the tumour from which they were derived. In the first TIL pilot study, 12 patients with metastatic melanoma or renal cell carcinoma (RCC) were treated with IL-2-expanded TILs and subsequent IL-2 stimulation with or without lymphodepleting cyclophosphamide chemotherapy prior to TIL infusion. Two patients in the cyclophosphamide group achieved a partial response.5 Since then, increased knowledge about TILs has led to remarkable progress in developing methods to expand them ex vivo, improving lymphodepleting conditioning and optimizing stimulation with IL-2. In 2011, Rosenberg et al.6 published the final analysis of three sequential clinical trials, demonstrating a response rate of 49–72%; 22% of metastatic melanoma patients achieved a complete response. When treated with TILs preceded by lymphodepleting chemotherapy and followed by high-dose bolus infusions of IL-2 the majority of the complete responses persisted years after treatment. ...

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