Engineered t cells targeting E7 mediate regression of human papillomavirus cancers in a murine model.

Jin, Benjamin Y.; Campbell, Tracy E.; Draper, Lindsey M.; Stevanović, Sanja; Weißbrich, Bianca; Yu, Zhiya; Restifo, Nicholas P.; Rosenberg, Steven A.; Trimble, Cornelia L.; Hinrichs, Christian S.

doi:10.1200/jco.2018.36.15_suppl.e15048

Cited by 18 publications

(40 citation statements)

References 45 publications

(103 reference statements)

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“…Although E7 11-20 has been identified as an immunodominant HLA-A Ã 0201 epitope (10), the E7 [11][12][13][14][15][16][17][18][19] peptide is also naturally processed and presented on cancer cells (11). Thus, it is significant that the two TCRs identified and tested from CUE-101 expanded CD8 þ T cells were able to recognize both the E7 11-20 and E7 [11][12][13][14][15][16][17][18][19] peptides, suggesting that if only one of these peptides is processed and presented in a given patient CUE-101 will expand a relevant CTL population. Therefore, CUE-101 has the potential to harness a diverse, native T-cell repertoire to mount an effective antitumor immune response while avoiding systemic activation of the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 2 to 4 Â 10 6 human PBMCs expanded with CUE-101 or peptide were pretreated with Brefeldin A (BFA) and Monensin (Thermofisher), plated in a 24-well plate, and stimulated at a 1:1 ratio with T2 cells (ATCC) that had been loaded with 5 mg/mL of E7 [11][12][13][14][15][16][17][18][19][20] (YMLDLQPETT) or HIV-1 p17 Gag 77-85 (SLYNTVATL; SL9) peptide for 2 hours and washed twice. Alternatively, 2 Â 10 6 murine cells were plated in a 96-well U-bottom plate and restimulated in CTL Test Medium containing 1% Glutamax by combining E7 49-57 peptide (RAHYNIVTF; 10 mg/mL) with BFA and Monensin diluted per the manufacturer's instructions.…”

Section: Intracellular Cytokine Stainingmentioning

confidence: 99%

“…SKW-3 cells (DSMZ) were cultured in complete RPMI1640 without pen-strep. TCR lentiviral construct design followed the method of Jin and colleagues (18), and the generation of stable TCR-expressing SKW-3 cells is described in the Supplementary Materials and Methods. Assessment of CD69 upregulation was performed by loading T2 cells with peptide and coincubating with stable TCR transduced SKW-3 cells overnight at 37 C. The cells were stained for CD3, CD19, live/ dead, and CD69 in the presence of Fc receptor inhibition, and analyzed.…”

Section: Tcr Sequencing and Analysis Of Stable T-cell Clonesmentioning

confidence: 99%

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CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies

Quayle¹,

Girgis²,

Thapa³

et al. 2020

Clinical Cancer Research

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Purpose: To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E7 11-20-specific CD8 þ T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical, and anal cancers. Experimental Design: CUE-101 is an Fc fusion protein composed of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human IL2 molecules, and an effector attenuated human IgG1 Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model. Results: CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E7 11-20-specific CD8 þ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E7 11-20-specific CD8 þ T cells in HLA-A2 (AAD) transgenic mice, and anticancer efficacy and immunologic memory was demonstrated in TC-1 tumor-bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy. Conclusions: Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E7 11-20-specific population of cytotoxic CD8 þ T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing phase I trial (NCT03978689).

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Section: Discussionmentioning

confidence: 99%

Section: Intracellular Cytokine Stainingmentioning

confidence: 99%

Section: Tcr Sequencing and Analysis Of Stable T-cell Clonesmentioning

confidence: 99%

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CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies

Quayle¹,

Girgis²,

Thapa³

et al. 2020

Clinical Cancer Research

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“…Approximately 15-20% of all cancers worldwide are associated with infection, the majority associated with viral infection 35 , whilst bacteria and multicellular parasites are responsible for only a fraction of these infection-related cancers 46 .…”

Section: Viral Infections and Virus-associated Malignanciesmentioning

confidence: 99%

“…Identification and sequencing of TCRs able to recognise epitopes expressed by human tumours together with improvements in TCR gene transfer technology have allowed for rapid redirection of T cells and targeting of a variety of tumour antigens, including gp100 28 , p53 29 , carcinoembryonic antigen (CEA) 28 , cancer-testis antigen (CTA) family members (e.g. NY-ESO-1 30 , MAGE-A3 31 , MAGE-A4 32 and MAGE-A10 33 ), and viral protein family members 34,35 .…”

mentioning

confidence: 99%

T-cell receptor gene-modified cells: past promises, present methodologies and future challenges

Rego

Morris²,

Lowdell

2019

Cytotherapy

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Immunotherapy constitutes an exciting and rapidly evolving field, and the demonstration that genetically-modified T cell receptors (TCRs) can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy.Overall, TCR-modified T cells have the ability to target a wide variety of self and non-self targets through the normal biology of a T cell. Although MHC-restricted and dependent on co-receptors, genetically engineered TCRs still present a number of characteristics that ensure they are an important alternative strategy to chimeric antigen receptors (CARs), and high affinity TCRs can now be successfully engineered with the potential to enhance therapeutic efficacy while minimising adverse events.This review will focus on the main characteristics of TCR gene-modified cells, their potential clinical application and promise to the field of adoptive cell transfer (ACT), basic manufacturing procedures and characterisation protocols, and overall challenges that need to be overcome so that redirection of TCR specificity may be successfully translated into clinical practice, beyond early phase clinical trials. BackgroundWith roots in the principles of basic immunology, synthetic biology and genetic engineering, the field of adoptive cell transfer (ACT) has become one of the most promising and innovative approaches to treat cancer, viral infections and other immune-modulated diseases.There are currently three main types of ACT using effector T cells 1 : administration of tumour infiltrating lymphocytes (TILs), and gene transfer-based strategies relying on genetic engineering to express either chimeric antigen (Ag) receptors (CARs) -composed of antibody (Ab)-binding domains fused to T cell signalling domains -or engineered T cell receptor (TCR) α/β heterodimers.Genetic modification of autologous T cells to target specific tumour antigens has been developed to overcome the consequences of immune tolerance and offers the possibility to endow the immune system with reactivities not naturally present. This approach has the additional benefit of rapid tumour eradication, which is usually observed with cytotoxic chemotherapy or other targeted therapies rather than the delayed responses that are commonly observed with vaccines and T cell checkpoint therapies. Page 2 of 33Durable anticancer responses have been extensively reported for CARs targeting CD19 in the treatment of acute lymphoblastic leukaemia (ALL), B-cell lymphomas 2 and chronic lymphocytic leukaemia (CLL), and the US Food and Drug Administration (FDA) has recently approved two genetically engineered CD19 CAR T cell products, tisagenlecleucel (Kymriah) 3 and axicabtagene ciloleucel (Yescarta) 4 , for clinical application. Therapeutic TCR gene-modified T cells have demonstrated clinical activity in earlier phase clinical trials but their development currently lags behind CAR T cells 2 . The unique biology of TCR-peptide/MHC recognition may render TCR-modified T cells a more suitable approach for specific t...

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SARS‐CoV‐2‐reactive T‐cell receptors isolated from convalescent COVID‐19 patients confer potent T‐cell effector function

et al. 2021

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Both B cells and T cells are involved in an effective immune response to SARS-CoV-2, the disease-causing virus of COVID-19. While B cells-with the indispensable help of CD4 + T cells-are essential to generate neutralizing antibodies, T cells on their own have been recognized as another major player in effective anti-SARS-CoV-2 immunity. In this report, we provide insights into the characteristics of individual HLA-A*02:01-and HLA-A*24:02restricted SARS-CoV-2-reactive TCRs, isolated from convalescent COVID-19 patients. We observed that SARS-CoV-2-reactive T-cell populations were clearly detectable in convalescent samples and that TCRs isolated from these T cell clones were highly functional upon ectopic re-expression. The SARS-CoV-2-reactive TCRs described in this report mediated potent TCR signaling in reporter assays with low nanomolar EC50 values. We further demonstrate that these SARS-CoV-2-reactive TCRs conferred powerful T-cell effector function to primary CD8 + T cells as evident by a robust anti-SARS-CoV-2 IFN-γ response and in vitro cytotoxicity. We also provide an example of a long-lasting anti-SARS-CoV-2 memory response by reisolation of one of the retrieved TCRs 5 months after initial sampling. Taken together, these findings contribute to a better understanding of anti-SARS-CoV-2

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Engineered t cells targeting E7 mediate regression of human papillomavirus cancers in a murine model.

Cited by 18 publications

References 45 publications

CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies

CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies

T-cell receptor gene-modified cells: past promises, present methodologies and future challenges

SARS‐CoV‐2‐reactive T‐cell receptors isolated from convalescent COVID‐19 patients confer potent T‐cell effector function

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