T Cells Targeting Carcinoembryonic Antigen Can Mediate Regression of Metastatic Colorectal Cancer but Induce Severe Transient Colitis

Parkhurst, Maria R.; Yang, James Chih‐Hsin; Langan, Russell C.; Dudley, Mark E.; Nathan, Debbie; Feldman, Steven A.; Davis, Jeremy L.; Morgan, Richard A.; Merino, María J.; Sherry, Richard M.; Hughes, Marybeth S.; Kammula, Udai S.; Phan, Giao Q.; Lim, Ramona M.; Wank, Stephen A.; Restifo, Nicholas P.; Robbins, Paul F.; Laurençot, Carolyn M.; Rosenberg, Steven A.

doi:10.1038/mt.2010.272

Cited by 872 publications

(727 citation statements)

References 32 publications

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“…The provision of characterized TCRs with different tumor antigen specificities and HLA restrictions may fuel the development of therapies based on vaccination or adoptive transfer of TCR-engineered T cells that have recently led to promising results (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Functional TCR Retrieval from Single Antigen-Specific Human T Cells Reveals Multiple Novel Epitopes

Simon

Omokoko

Breitkreuz

et al. 2014

Cancer Immunology Research

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The determination of the epitope specificity of disease-associated T-cell responses is relevant for the development of biomarkers and targeted immunotherapies against cancer, autoimmune, and infectious diseases. The lack of known T-cell epitopes and corresponding T-cell receptors (TCR) for novel antigens hinders the efficient development and monitoring of new therapies. We developed an integrated approach for the systematic retrieval and functional characterization of TCRs from single antigen-reactive T cells that includes the identification of epitope specificity. This is accomplished through the rapid cloning of full-length TCR-a and TCR-b chains directly from single antigen-specific CD8 þ or CD4 þ T lymphocytes. The functional validation of cloned TCRs is conducted using in vitro-transcribed RNA transfer for expression of TCRs in T cells and HLA molecules in antigen-presenting cells. This method avoids the work and bias associated with repetitive cycles of in vitro T-cell stimulation, and enables fast characterization of antigen-specific T-cell responses. We applied this strategy to viral and tumor-associated antigens (TAA), resulting in the retrieval of 56 unique functional antigenspecific TCRs from human CD8 þ and CD4 þ T cells (13 specific for CMV-pp65, 16 specific for the well-known TAA NY-ESO-1, and 27 for the novel TAA TPTE), which are directed against 39 different epitopes. The proof-of-concept studies with TAAs NY-ESO-1 and TPTE revealed multiple novel TCR specificities. Our approach enables the rational development of immunotherapy strategies by providing antigen-specific TCRs and immunogenic epitopes.

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Section: Discussionmentioning

confidence: 99%

Functional TCR Retrieval from Single Antigen-Specific Human T Cells Reveals Multiple Novel Epitopes

Simon

Omokoko

Breitkreuz

et al. 2014

Cancer Immunology Research

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“…redirected PBLs can mediate tumor regression and may have a significant advantage over TILs in that PBLs can be targeted to a variety of cancers on the basis of the availability of a tumor-specific TCR or CAR ( Johnson et al, 2006( Johnson et al, , 2009Morgan et al, 2006;Brentjens et al, 2011;Kochenderfer et al, 2011;Parkhurst et al, 2011;Porter et al, 2011;Robbins et al, 2011;Savoldo et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…For ex vivo gene therapy protocols, peripheral blood lymphocytes (PBLs) can be genetically modified to express a tumor-reactive T cell receptor (TCR) or chimeric antigen receptor (CAR) directed against antigens including, but not limited to, MART (melanoma antigen recognized by T cells)-1, gp100, carcinoembryonic antigen (CEA), NY-ESO-1, CD19, or other tumor antigens. In initial phase I/II clinical trials with limited numbers of patients treated, response rates ranged between 13 and 100% (Morgan et al, 2006;Kochenderfer et al, 2010;Kalos et al, 2011;Parkhurst et al, 2011;Porter et al, 2011;Robbins et al, 2011). Importantly, genetically modified PBLs can mediate tumor regression and can be redirected against a variety of cancers on the basis of the availability of tumorspecific TCRs or CARs.…”

Section: Introductionmentioning

confidence: 99%

A Simple and Effective Method to Generate Lentiviral Vectors forEx VivoGene Delivery to Mature Human Peripheral Blood Lymphocytes

Yang

Karne

Goff

et al. 2012

Human Gene Therapy Methods

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Human ex vivo gene therapy protocols have been used successfully to treat a variety of genetic disorders, infectious diseases, and cancer. Murine oncoretroviruses (specifically, gammaretroviruses) have served as the primary gene delivery vehicles for these trials. However, in some cases, such vectors have been associated with insertional mutagenesis. As a result, alternative vector platforms such as lentiviral vectors (LVVs) are being developed. LVVs may provide advantages compared with gammaretroviral vectors, including the ability to transduce large numbers of nondividing cells, resistance to gene silencing, and a potentially safer integration profile. The aim of this study was to develop a simplified process for the rapid production of clinical-grade LVVs. To that end, we used a self-inactivating bicistronic LVV encoding an MART (melanoma antigen recognized by T cells)-1-reactive T cell receptor containing oPRE, an optimized and truncated version of woodchuck hepatitis virus posttranslational regulatory element (wPRE). Using our simplified clinical production process, 293T cells were transiently transfected in roller bottles. The LVV supernatant was collected, treated with Benzonase, and clarified by modified step filtration. LVV produced in this manner exhibited titers and a biosafety profile similar to those of cGMP (current Good Manufacturing Practices) LVVs previously manufactured at the Indiana University Vector Production Facility in support of a phase I/II clinical trial. We describe a simple, efficient, and low-cost method for the production of clinical-grade LVV for ex vivo gene therapy protocols.

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“…Since then, other trials have tested TCRs against other antigens, including gp100 in melanoma (13), carcinoembryonic antigen (CEA) in colorectal cancer (14), and NY-ESO-1 (15) and MAGE-A3 (16) in melanoma and synovial sarcoma. Clinical responses were observed across trials.…”

Section: Tcr T Cells Tcr T Cells Are T Cells Cloned With Tcrs In Whichmentioning

confidence: 99%

T-cell–based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition

Houot

Schultz

Marabelle

et al. 2015

Cancer Immunology Research

163

121

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Tumor immunotherapy has had demonstrable efficacy in patients with cancer. The most promising results have been with T-cell-based therapies. These include adoptive cell transfer of tumor-infiltrating lymphocytes, genetically engineered T cells, and immune checkpoint inhibitor antibodies. In this review, we describe the different T-cell-based strategies currently in clinical trials and put their applications, present and future, into perspective.

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T Cells Targeting Carcinoembryonic Antigen Can Mediate Regression of Metastatic Colorectal Cancer but Induce Severe Transient Colitis

Cited by 872 publications

References 32 publications

Functional TCR Retrieval from Single Antigen-Specific Human T Cells Reveals Multiple Novel Epitopes

Functional TCR Retrieval from Single Antigen-Specific Human T Cells Reveals Multiple Novel Epitopes

A Simple and Effective Method to Generate Lentiviral Vectors forEx VivoGene Delivery to Mature Human Peripheral Blood Lymphocytes

T-cell–based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition

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