Adoptive cell transfer: a clinical path to effective cancer immunotherapy

Abstract

Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective cancer regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment.

Figure 1. The generation of anti-tumour T cells used for adoptive cell therapy

A tumour is excised and multiple individual cultures are established, separately grown and assayed for specific tumour recognition. Cultures with high anti-tumour reactivity are expanded to large numbers (>10¹⁰ cells) and reinfused into the cancer patient following the administration of a conditioning lymphodepleting chemotherapy. IL2, interleukin 2.

Figure 2. Examples of objective tumour regressions in patients receiving adoptive cell transfer of autologous anti-tumour lymphocytes following a lymphodepleting preparative regimen

In each case the pretreatment scans and photos are shown on the left and the post-treatment on the right. a | A 45-year-old male with metastatic melanoma to the liver (upper) and right adrenal gland (middle) who was refractory to prior treatment with high dose α interferon as well as high-dose interleukin 2 (IL2). He underwent a rapid regression of metastases and developed vitiligo (lower). b | A 55-year-old male with rapid tumour growth in the axilla as well as multiple brain metastases from metastatic melanoma that was refractory to prior treatment with high dose IL2 who underwent rapid regression of nodal and brain metastases.

Figure 3. The steps involved in generating anti-tumour T cells by inserting genes encoding T-cell receptors

Highly avid anti-tumour T cells are identified and the genes encoding their T-cell receptors (TCRs) are cloned and inserted into retroviruses. Retroviral supernatants are then produced under good manufacturing practice (GMP) conditions and used to insert the T-cell receptors into normal lymphocytes. Expression of the T-cell receptor is then compared in untransduced (UnTd) and transduced (Td) cells by fluorescence-activated cell sorting analysis and by recognition in vitro of HLA-A2⁺ 526 melanoma line and not the HLA-A2⁻ 888 melanoma line. The effector cells were the anti-MART JKF6 line and untransduced (PBL) and transduced (TCR) lymphocytes. C, constant; IRES, internal ribosome entry site; LTR, long terminal repeat; SA, splice acceptor site; SD, splice donor site; V, variable. Steps 3 and 5 reproduced, with permission, from REF. 4 © American Association for the Advancement of Science (2006).

Figure 4. Diagram of the retroviral constructs used to insert T-cell receptor (TCR) genes in T cells

T cells can be engineered with two classes of receptor proteins that are capable of recognizing tumour-associated antigens. Naturally occurring TCRs require coordinated expression of an α and β chain, which can be facilitated by an internal ribosome entry site (IRES) or by the use of a 2A fusion protein. A chimeric antigen receptor is an artificially constructed hybrid protein containing the antigen-binding domains of a single-chain antibody (scFv) linked to T-cell signal domains, such as CD28 and CD3ζ. Vector-specific cis-acting sequences are the long terminal repeat (LTR) that contains the enhancer, promoter and polyadenylation sites, splice donor (SD) and splice acceptor (SA) sequences, and packaging signal (ψ). The target antigen for each of these vectors is as indicated.

Timeline 1. Selected highlights in the development of ACT in animal models

ACT, adoptive cell therapy; IL2, interleukin 2; TCR, T-cell receptor.

Timeline 2. Examples of ACT in patients with cancer

EBV, Epstein–Barr virus; PTLD, post-transplant lymphoproliferative disease; TCR, T-cell receptor; TIL, tumour-infiltrating lymphocytes.