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Adoptive cell transfer: a clinical path to effective cancer immunotherapy - PubMed

Review

Adoptive cell transfer: a clinical path to effective cancer immunotherapy

Steven A Rosenberg et al. Nat Rev Cancer. 2008 Apr.

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.

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Figures

Figure 1
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
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
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
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
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
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.

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References

    1. Rosenberg SA, et al. Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. Preliminary report. N. Engl. J. Med. 1988;319:1676–1680.The first paper to demonstrate the regression of cancer using TIL for the immunotherapy of patients with metastatic melanoma.

    1. Dudley ME, et al. Cancer regression and autoimmunity in patients following clonal repopulation with anti-tumor lymphocytes. Science. 2002;298:850–854. - PMC - PubMed

    1. Dudley ME, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 2005;23:2346–2357.Reference 2 and Reference 3 demonstrate that lymphodepletion prior to ACT can lead to increased cancer regression as well as clonal repopulation of patients with anti-tumour lymphocytes.

    1. Morgan RA, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126–129.The first paper demonstrating the adoptive cell transfer of lymphocytes transduced with a retrovirus encoding TCRs that recognize a cancer antigen can mediate anti-tumour responses in patients with metastatic melanoma.

    1. Rosenberg SA, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 1985;313:1485–1492. - PubMed

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