Strategies to genetically engineer T cells for cancer immunotherapy

Spear, Timothy T.; Nagato, Kaoru; Nishimura, Michael I.

doi:10.1007/s00262-016-1842-5

Cited by 45 publications

(45 citation statements)

References 185 publications

(188 reference statements)

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“…Adoptive cell transfer (ACT) of T cell receptor (TCR) gene-modified T-cells has had mixed, but promising clinical results as a cancer immunotherapy [1]. To enhance the efficacy/safety of TCR gene-modified T-cells, the field should continually refine the fundamental understanding of antigen recognition, which is generally thought to be dictated by the affinity and specificity of the interaction between TCR and peptide-major histocompatibility complex proteins (pMHC) [2].…”

Section: Introductionmentioning

confidence: 99%

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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T cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR-pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR-pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR-pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR-pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.

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Section: Introductionmentioning

confidence: 99%

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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“…Although the use of peptide vaccines may not be optimal to treat tumors expressing low levels of MHC, some molecule-targeted therapies such as EGFR and MEK inhibitors increase MHC expression on tumors and could be combined with peptide vaccines [20,21]. Since aberrantly high-affinity TCRs produced by gene-modification can induce severe adverse effects [22], vaccine-induced endogenous T cells would be a more suitable way to treat cancer without toxicities.…”

Section: Advantages and Disadvantages Of Peptide Vaccines Compared Tomentioning

confidence: 99%

Peptide vaccines in cancer — old concept revisited

Kumai

Kobayashi

Harabuchi

et al. 2017

Current Opinion in Immunology

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Synthetic peptide vaccines aim to elicit and expand tumor-specific T cells capable of controlling or eradicating the tumor. Despite the high expectations based on preclinical studies, the results of clinical trials using peptide vaccines have been disappointing. Thus, many researchers in the field have considered peptide vaccines as outdated and no longer viable for cancer therapy. However, recent progress in understanding the critical roles of immune adjuvants, modes of vaccine administration and T cell dynamics has lead to a rebirth of this approach and reconsidering the use of peptide vaccines for treating malignant disorders.

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“…These are T cells that have been transduced with a genetically engineered T-cell receptor with a specific, targeted extracellular antigen recognition domain, a transmembrane domain, and an intracellular signaling domain 177. Even though CAR T cells have shown great promise in hematologic malignancies, this success has not yet been translated to solid tumors or sarcomas.…”

Section: Immunotherapymentioning

confidence: 99%

Targeted therapy for soft tissue sarcomas in adolescents and young adults

Steppan

Pratilas

Loeb

2017

AHMT

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Soft tissue sarcomas (STSs) are a heterogeneous group of tumors originating from the mesenchyme. Even though they affect individuals in all age groups, the prevalence of subtypes of STSs changes significantly from childhood through adolescence into adulthood. The mainstay of therapy is surgery, with or without the addition of chemotherapy and/or radiation therapy. These treatment modalities are associated, in many cases, with significant morbidity and, given the heterogeneity of tumor histologies encompassed by the term “STS”, have not uniformly improved outcomes. Moreover, some subgroups of STSs appear to be more, and others less, responsive to conventional chemotherapy agents. Over the last two decades, our understanding of the biology of STSs is slowly increasing, allowing for the development of more targeted therapies. We review the new treatment modalities that have been tested on patients with STSs, with a special focus on adolescents and young adults, a group of patients that is often underrepresented in clinical trials and has not received the dedicated attention it deserves, given the significant differences in biology and treatment response in comparison to children and adults.

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Strategies to genetically engineer T cells for cancer immunotherapy

Cited by 45 publications

References 185 publications

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Peptide vaccines in cancer — old concept revisited

Targeted therapy for soft tissue sarcomas in adolescents and young adults

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