T cell receptor (TCR) gene therapy to treat melanoma: lessons from clinical and preclinical studies

Coccoris, Miriam; Straetemans, Trudy; Govers, Coen; Lamers, Cor H.J.; Sleijfer, Stefan; Debets, Reno

doi:10.1517/14712591003614756

Cited by 35 publications

(27 citation statements)

References 144 publications

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“…6,39 Improving T cell persistence is yet another important goal of receptor gene therapy. 24,25,40 Here, we may have prevented on-target toxicity through CAIX mAb pre-treatment, which at the lowest T cell dose (total 1 × 10 9 CAR T cells) coincided with reduced humoral and cellular immunity directed against CAR T cells and an apparent improvement of the peripheral persistence. Future strategies to improve T cell persistence should include pre-selection and controlled in vitro propagation of T cells to generate T cells with preferred less differentiated phenotype, in combination with a patient lymphodepleting preconditioning regimen.…”

Section: Discussionmentioning

confidence: 86%

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Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

et al. 2013

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Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 × 10(9) CAR T cells. CTC grade 2-4 liver enzyme disturbances occurred at the lowest CAR T cell doses, necessitating cessation of treatment in four out of eight patients in cohorts 1 and 2. Examination of liver biopsies revealed CAIX expression on bile duct epithelium with infiltration of T cells, including CAR T cells. Subsequently four patients were pre-treated with CAIX monoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed no liver toxicities and indications for enhanced peripheral T cell persistence. No clinical responses were recorded. This report shows that CAIX-targeting CAR T cells exerted antigen-specific effects in vivo and induced liver toxicity at the lowest dose of 0.2 × 10(9) T cells applied, illustrating the potency of receptor-modified T cells. We provide in-patient proof that the observed "on-target" toxicity is antigen-directed and can be prevented by blocking antigenic sites in off-tumor organs and allowing higher T cell doses.

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Section: Discussionmentioning

confidence: 86%

“…Future strategies to improve T cell persistence should include pre-selection and controlled in vitro propagation of T cells to generate T cells with preferred less differentiated phenotype, in combination with a patient lymphodepleting preconditioning regimen. 14,24,25,40 …”

Section: Discussionmentioning

confidence: 99%

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

et al. 2013

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“…The limited therapeutic effectiveness of CAR-or TCRtransduced T cells may result, among others, 10 from the potential immunogenicity of the chimeric receptor transgenes. In immunecompetent hosts, the adoptive transfer of gene-modified immune effector cells may induce immune responses against the transgene, [11][12][13][14] resulting in limited persistence and hence limited antitumor effects of transferred gene-modified cells.…”

Section: Introductionmentioning

confidence: 99%

Immune responses to transgene and retroviral vector in patients treated with ex vivo–engineered T cells

Lamers

Willemsen

Elzakker

et al. 2011

Blood

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Adoptive transfer of immune effector cells that are gene modified by retroviral transduction to express tumor-specific receptors constitutes an attractive approach to treat cancer. In patients with metastatic renal cell carcinoma, we performed a study with autologous T cells genetically retargeted with a chimeric antibody receptor (CAR) directed toward carbonic anhydrase IX (CAIX), an antigen highly expressed in renal cell carcinoma. In the majority of patients, we observed distinct humoral and/or cellular anti-CAIX-CAR

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“…However, these methods are technically challenging, difficult to standardize, and not generalizable to all patient specimens. One potential way to overcome this hurdle is to engineer the transferred cells to express TCRs known to be specific for tumor antigens (3)(4)(5). Methods for introducing tumor antigen-specific TCR genes into PBMCs have been developed, and a clinical study transferring PBMCs engineered to express a TCR specific for the melanoma antigen MART-1 combined with peptide-pulsed DCs is underway.…”

Section: Advances In the Development Of Cancer Immunotherapiesmentioning

confidence: 99%

Tumor Immunology: Basic and Clinical Advances

Beatty

Cascio

2011

Cancer Research

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The third in a series of AACR conferences, entitled "Tumor Immunology: Basic and Clinical Advances," was held in Miami Beach, Florida from November 30 to December 3, 2010. The overall objective of this meeting was to discuss rapid developments in the understanding of basic principles of antitumor immunity and strategies for increasing the success rate of cancer immunotherapy. The key findings that emerged from the meeting included (i) that integrated approaches are required for the development of effective cancer immunotherapies and (ii) attention should be on multiple cellular and molecular components and their broader networks rather than on a single pathway or cell type. Cancer Res; 71(13); 4338-43. '2011 AACR.

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T cell receptor (TCR) gene therapy to treat melanoma: lessons from clinical and preclinical studies

Abstract: To ensure further clinical development of TCR gene therapy, it is necessary to choose safe T cell target antigens, and implement (combinations of) strategies that enhance the correct pairing of TCR transgenes and the functional avidity and persistence of T cells.

Cited by 35 publications

References 144 publications

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

Immune responses to transgene and retroviral vector in patients treated with ex vivo–engineered T cells

Tumor Immunology: Basic and Clinical Advances

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