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Adoptive cell transfer: a clinical path to effective cancer immunotherapy

Nature Reviews Cancer volume 8, pages 299–308 (2008)Cite this article

Key Points

  • Adoptive cell therapy (ACT) is a treatment that uses a cancer patient's own T lymphocytes with anti-tumour activity, expanded in vitro and reinfused into the patient with cancer.

  • ACT using autologous tumour-infiltrating lymphocytes is currently the most effective treatment for patients with metastatic melanoma and can mediate objective tumour regressions in 50% of patients.

  • Lymphodepletion before ACT is an important component of the treatment because it eliminates T regulatory cells and eliminates lymphocytes, which compete with the transferred cells for homeostatic cytokines such as interleukin 7 (IL7) and IL15.

  • ACT can be effective in treating selected patients with post-transplant lymphoproliferative diseases (PTLD) resulting from Epstein–Barr virus, which can cause PTLD during the immunosuppressed state.

  • Recent studies have shown that genetic modification of lymphocytes using retroviruses that encode T-cell receptors can convert normal lymphocytes into lymphocytes with anti-cancer activity. The adoptive transfer of these lymphocytes into patients with metastatic melanoma can mediate tumour regression.

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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Figure 1: The generation of anti-tumour T cells used for adoptive cell therapy.
Figure 2: Examples of objective tumour regressions in patients receiving adoptive cell transfer of autologous anti-tumour lymphocytes following a lymphodepleting preparative regimen.
Figure 3: The steps involved in generating anti-tumour T cells by inserting genes encoding T-cell receptors.
Figure 4: Diagram of the retroviral constructs used to insert T-cell receptor (TCR) genes in T cells.

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Authors and Affiliations

  1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, 20892, Maryland, USA

    Steven A. Rosenberg, Nicholas P. Restifo, James C. Yang, Richard A. Morgan & Mark E. Dudley

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Correspondence to Steven A. Rosenberg.

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DATABASES

National Cancer Institute

chronic myeloid leukaemia

melanoma

multiple myeloma

nasopharyngeal cancer

renal cancer

National Cancer Institute Drug Dictionary

cyclophosphamide

fludarabine

Glossary

Adoptive cell therapy

(ACT). The administration of a patient's own (autologous) or donor (allogeneic) anti-tumour lymphocytes following a lymphodepleting preparative regimen.

Capillary leak syndrome

The loss of intravascular fluid into soft tissues and lung.

Objective clinical response

The Response Evaluation Criteria in Solid Tumours (RECIST) defines an objective response as a 30% reduction in the sum of the longest diameters of measurable lesions comparing post-treatment with pretreatment values. The World Health Organization criterion defines an objective response to be a 50% reduction in the sum of the products of perpendicular diameters of measurable lesions. In both criteria no new lesions can appear.

Avidity

The relative intensity of reactivity of lymphocytes when interacting with antigen.

Allogeneic

Inter-individual genetic variation at the MHC locus. In a partially matched transplant, for example, some MHC antigens are shared by donor and recipient, but in addition the donor has some MHC antigens that the recipient does not.

Lymphodepletion

Lymphodepletion before ACT uses total body irradiation or cytotoxic drugs to deplete the lymphoid compartment of patients.

Central memory cells

A subset of antigen-reactive lymphocytes with markers such as CD62L and CCR7 that indicate a less differentiated phenotype.

Antigen-presenting cells

(APC). A subset of cells that have characteristics enabling them to efficiently present antigenic epitopes to lymphocytes (for example, dendritic cells).

Non-myeloablative

Relatively modest to moderate doses of chemotherapy are given, not to attack the cancer, but just to suppress the immune system for a brief period of a week or so.

Effector phenotype

A constellation of cell surface markers that indicate that lymphocytes have differentiated into a mature effector cell capable of recognizing antigen and lysing target cells or secreting cytokines when encountering antigen.

Alloantigens

An antigen that exists in alternative (allelic) forms in a species, thus inducing an immune response when one form is transferred to members of the species who lack it.

Buffy coat cells

The plasma layer containing enriched white blood cells that results when whole blood is centrifuged.

Chronic phase

Indolent phase of the disease in patients with chronic myeloid leukaemia.

Blast crisis

Aggressive acute phase of the disease in patients with chronic myeloid leukaemia.

Graft-versus-host disease

Inflammatory and tissue-destructive immune reactions that result from the attack on host tissues by infused allogeneic lymphocytes.

Post-transplant lymphoproliferative disease

(PTLD). Neoplastic proliferation of lymphocytes that occurs in patients undergoing immunosuppresion, often in preparation for bone marrow or organ transplantation; can occur in host or recipient cells.

Reed–Sternberg cells

Cells with a characteristic morphology that are thought to be the malignant cells in patients with Hodgkin lymphoma.

Tolerance

The process that ensures that B- and T-cell repertoires are biased against self-reactivity, reducing the likelihood of autoimmunity.

Carcinoembryonic antigen

A protein found in fetal gastrointestinal tissue that can be upregulated in some gastrointestinal cancers and can serve as a marker of tumour burden.

Cancer–testis antigen

A class of antigenic proteins present on some human cancers but not on adult normal tissues except for testes.

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Rosenberg, S., Restifo, N., Yang, J. et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8, 299–308 (2008). https://doi.org/10.1038/nrc2355

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