Adoptive Immunotherapy of Human Diseases with Antigen-Specific T-Cell Clones

Riddell, Stanley R.; Warren, Edus H.; Lewinsohn, Deborah A.; Brodie, Scott J.; Fries, R de; Corey, Lawrence; Greenberg, Philip D.

doi:10.1007/978-4-431-68506-7_3

Cited by 4 publications

(5 citation statements)

References 38 publications

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“…ACT involves the transfer of ex vivo expanded tumor-infiltrating effector cells as a means of augmenting the antitumor immune response and has been employed in the context of human melanoma [103]. In contrast to tumor vaccination strategies, ACT can allow for far greater control over the magnitude and avidity of the targeted response by appropriate manipulation and selection in vitro of the T cells used for therapy [104,105]. Tumor-reactive effector cells of a desired specificity and phenotype can be identified in vitro , selected based on expression of a high-affinity receptor and specific surface markers, and expanded to very high numbers.…”

Section: Adoptive Transfer Therapy and Epigenetic Modulatory Drugsmentioning

confidence: 99%

Regulation of Cancer Germline Antigen Gene Expression: Implications for Cancer Immunotherapy

2010

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Cancer germline (CG; also known as cancer-testis) antigen genes are normally expressed in germ cells and trophoblast tissues and are aberrantly expressed in a variety of human malignancies. CG antigen genes have high clinical relevance as they encode a class of immunogenic and highly selective tumor antigens. CG antigen-directed immunotherapy is undergoing clinical evaluation for the treatment of a number of solid tumor malignancies and has been demonstrated to be safe, provoke immune responses and be of therapeutic benefit. Achieving an improved understanding of the mechanisms of CG antigen gene regulation will facilitate the continued development of targeted therapeutic approaches against tumors expressing these antigens. Substantial evidence suggests epigenetic mechanisms, particularly DNA methylation, as a primary regulator of CG antigen gene expression in normal and cancer cells as well as in stem cells. The roles of sequence-specific transcription factors and signal transduction pathways in controlling CG antigen gene expression are less clear but are emerging. A combinatorial therapeutic approach involving epigenetic modulatory drugs and CG antigen immunotherapy is suggested based on these data and is being actively pursued. In this article, we review the mechanisms of CG antigen gene regulation and discuss the implications of these mechanisms for the development of cancer immunotherapy approaches targeting CG antigens.

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Section: Adoptive Transfer Therapy and Epigenetic Modulatory Drugsmentioning

confidence: 99%

Regulation of Cancer Germline Antigen Gene Expression: Implications for Cancer Immunotherapy

2010

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“…To sustain the survival of activated lymphocytes following in vivo administration, it has been necessary to supply an exogenous source of IL-2, although the systemic toxicity of IL-2 severely limits the amount of this cytokine that can be given (6). Although multiple studies of the adoptive transfer of activated lymphocytes with specific function to humans with HIV infection and cancer have been attempted, the limited survival of these cells in vivo has severely compromised their function (4,(7)(8)(9)(10)(11). One potential solution to this problem is the introduction of genes into lymphocytes that can result in either the regulated or constitutive production of appropriate growth signals that might obviate the need for the administration of potentially toxic levels of administered cytokines.…”

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confidence: 99%

Transduction of an IL-2 Gene into Human Melanoma-Reactive Lymphocytes Results in Their Continued Growth in the Absence of Exogenous IL-2 and Maintenance of Specific Antitumor Activity

Liu

Rosenberg

2001

The Journal of Immunology

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IL-2-dependent activated cells undergo apoptotic death when IL-2 is withdrawn either in vitro or after in vivo cell transfer. To attempt to sustain their survival after IL-2 withdrawal, melanoma-reactive human T lymphocytes were retrovirally transduced with an exogenous human IL-2 gene. Transduced PBMC and cloned CD8+ T cells produced IL-2 and maintained viability after IL-2 withdrawal. Upon restimulation, IL-2 transductants proliferated in the absence of exogenous IL-2 and could be actively grown, and their survival could be maintained without added IL-2 for over 8 wk. PBMCs similarly transduced with a control vector did not produce IL-2 and failed to proliferate in the absence of IL-2. A CD8+ T cell clone, when transduced with an IL-2 gene, manifested the same phenotypes as PBMCs in the absence of exogenous IL-2. Furthermore, an Ab reactive with the α-chain of IL-2R complex reduced the viability mediated by IL-2 secretion of the IL-2 transductants. Moreover, transduction of an IL-2 gene did not affect the high degree of recognition and specificity of transductants against melanoma targets. These tumor-reactive IL-2 transductants may be valuable for in vitro studies and for improved adoptive transfer therapies for patients with metastatic melanoma.

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“…120,121 Antigen-specific cytotoxic cells that do specifically recognize tumor cells can be generated by cell cloning techniques ex vivo or can be genetically engineered by the stable transfection of a TCR that specifically recognizes a certain MHC-tumor antigen complex. 122,123 This has been made possible by the use of defined tumor antigens to stimulate lymphocytes in vitro, and the ability to clone lymphocytes derived from a single, antigenspecific T cell. 124 Adoptive transfer of clonally expanded lymphocytes to lymphopenic hosts after nonmyeloablative conditioning chemotherapy has resulted in cell proliferation and persistent clonal repopulation correlated with tumor regressions in patients with melanoma.…”

Section: Stimulation Of Effector Cellsmentioning

confidence: 99%

“…Moreover, the TCR of cytotoxic T cells can be substituted with an immunoglobulin-like surface molecule, which allows the binding to tumor-specific surface molecules not presented by MHC molecules. 122 These more elaborate forms of adoptive transfer of killer cells are being studied in ongoing clinical trials.…”

Section: Stimulation Of Effector Cellsmentioning

confidence: 99%

Current Developments in Cancer Vaccines and Cellular Immunotherapy

Ribas

Butterfield

Glaspy

et al. 2003

JCO

274

213

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This article reviews the immunologic basis of clinical trials that test means of tumor antigen recognition and immune activation, with the goal to provide the clinician with a mechanistic understanding of ongoing cancer vaccine and cellular immunotherapy clinical trials. Multiple novel immunotherapy strategies have reached the stage of testing in clinical trials that were accelerated by recent advances in the characterization of tumor antigens and by a more precise knowledge of the regulation of cell-mediated immune responses. The key steps in the generation of an immune response to cancer cells include loading of tumor antigens onto antigen-presenting cells in vitro or in vivo, presenting antigen in the appropriate immune stimulatory environment, activating cytotoxic lymphocytes, and blocking autoregulatory control mechanisms. This knowledge has opened the door to antigen-specific immunization for cancer using tumor-derived proteins or RNA, or synthetically generated peptide epitopes, RNA, or DNA. The critical step of antigen presentation has been facilitated by the coadministration of powerful immunologic adjuvants, the provision of costimulatory molecules and immune stimulatory cytokines, and the ability to culture dendritic cells. Advances in the understanding of the nature of tumor antigens and their optimal presentation, and in the regulatory mechanisms that govern the immune system, have provided multiple novel immunotherapy intervention strategies that are being tested in clinical trials.

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Adoptive Immunotherapy of Human Diseases with Antigen-Specific T-Cell Clones

Cited by 4 publications

References 38 publications

Regulation of Cancer Germline Antigen Gene Expression: Implications for Cancer Immunotherapy

Regulation of Cancer Germline Antigen Gene Expression: Implications for Cancer Immunotherapy

Transduction of an IL-2 Gene into Human Melanoma-Reactive Lymphocytes Results in Their Continued Growth in the Absence of Exogenous IL-2 and Maintenance of Specific Antitumor Activity

Current Developments in Cancer Vaccines and Cellular Immunotherapy

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