IL7-Fc Enhances the Efficacy of Adoptive T Cell Therapy under Lymphopenic Conditions in a Murine Melanoma Model

Adoptive cell therapy (ACT) using tumor-reactive T cells is a promising form of immunotherapy to specifically target cancer. However, the survival and functional maintenance of adoptively transferred T cells remains a challenge, ultimately limiting their efficacy. Here, we evaluated the use of recombinant IL7-Fc in ACT. In a lymphopenic murine melanoma model, IL7-Fc treatment led to the enhanced inhibition of tumor growth with an increased number of adoptively transferred CD8+ T cells in tumor tissue and tumor-draining lymph nodes. Additionally, IL7-Fc further enhanced anti-tumor responses that were induced by recombinant human IL2 in the same mouse model. In contrast, in an immunocompetent murine melanoma model, IL7-Fc dampened the anti-tumor immunity. Further, IL7-Fc decreased the proliferation of adoptively transferred and immune-activated tumor-reactive CD8+ T cells in immunocompetent mice by inducing the massive expansion of endogenous T cells, thereby limiting the space for adoptively transferred T cells. Our data suggest that IL7-Fc is principally beneficial for enhancing the efficacy of tumor-reactive T-cells in lymphopenic conditions for the ACT.

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An Update on Adoptive T-Cell Therapy and Neoantigen Vaccines

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_238001 ◽

2019 ◽

pp. e70-e78 ◽

Cited By ~ 11

Author(s):

Patrick A. Ott ◽

Gianpietro Dotti ◽

Cassian Yee ◽

Stephanie L. Goff

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Adoptive Cell Therapy ◽

Adoptive T Cell Therapy ◽

Clinical Activity ◽

Single Chain ◽

T Cell Therapy ◽

Substantial Impact ◽

Mhc Molecules

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has demonstrated long-lasting antitumor activity in select patients with advanced melanoma. Cancer vaccines have been used for many decades and have shown some promise but overall relatively modest clinical activity across cancers. Technological advances in genome sequencing capabilities and T-cell engineering have had substantial impact on both adoptive cell therapy and the cancer vaccine field. The ability to identify neoantigens—a class of tumor antigens that is truly tumor specific and encoded by tumor mutations through rapid and relatively inexpensive next-generation sequencing—has already demonstrated the critical importance of these antigens as targets of antitumor-specific T-cell responses in the context of immune checkpoint blockade and other immunotherapies. Therapeutically targeting these antigens with either adoptive T-cell therapy or vaccine approaches has demonstrated early promise in the clinic in patients with advanced solid tumors. Chimeric antigen receptor (CAR) T cells, which are engineered by fusing an antigen-specific, single-chain antibody (scFv) with signaling molecules of the T-cell receptor (TCR)/CD3 complex creating an antibody-like structure on T cells that recognizes antigens independently of major histocompatibility complex (MHC) molecules, have demonstrated remarkable clinical activity in patients with advanced B-cell malignancies, leading to several approvals by the U.S. Food and Drug Administration (FDA).

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A phase Ia/Ib, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps3151 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS3151-TPS3151

Author(s):

Bartosz Chmielowski ◽

Samuel Ejadi ◽

Roel Funke ◽

Todd Stallings-Schmitt ◽

Mitch Denker ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Cell ◽

Cell Therapy ◽

Solid Tumors ◽

Cd8 T Cells ◽

Adoptive T Cell Therapy ◽

Autologous Tumor ◽

T Cell Therapy ◽

Trial Phase

TPS3151 Background: Neoepitopes (neoE) derived from private tumor-exclusive mutations represent compelling targets for personalized TCR-T cell therapy. An ultra-sensitive and high-throughput process was developed to capture tumor mutation-targeted CD8 T cells from patient blood. NeoTCRs cloned from the captured CD8 T cells, when engineered into fresh CD8 and CD4 T cells, effected killing of patients’ autologous tumor cells in vitro. These observations have been leveraged for the development of a fully personalized adoptive T cell therapy (NeoTCR-P1). A Phase 1 clinical trial testing NeoTCR-P1 in subjects with solid tumors is ongoing (NCT03970382). Methods: During the initial trial phase, escalating doses of NeoTCR-P1 T cells administered without and with IL-2 in the regimen, and following conditioning chemotherapy, will be evaluated in subjects with advanced or metastatic solid tumors (melanoma, urothelial cancer, colorectal cancer, ovarian cancer, HR+ breast cancer, and prostate cancer). The objective of the Phase 1a study is to establish a recommended Phase 2 dose. Primary endpoints include the incidence and nature of DLTs and overall process feasibility. The proliferation, persistence, and trafficking of NeoTCR-T cells will be characterized. In the expansion trial phase, preliminary anti-tumor activity of NeoTCR-P1 will be assessed in selected tumors. The combination of NeoTCR-P1 dosing plus nivolumab will be tested in a Phase 1b study. Conclusion: This is the first clinical study of an autologous, fully personalized adoptive T cell therapy directed against private tumor-exclusive mutations, generated without using recombinant viral vectors. Clinical trial information: NCT03970382 .

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IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors

Blood ◽

10.1182/blood-2012-05-431718 ◽

2013 ◽

Vol 121 (4) ◽

pp. 573-584 ◽

Cited By ~ 265

Author(s):

Nicoletta Cieri ◽

Barbara Camisa ◽

Fabienne Cocchiarella ◽

Mattia Forcato ◽

Giacomo Oliveira ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Adoptive Cell Therapy ◽

Cell Subset ◽

Gene Expression Signature ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

Hematopoietic Stem ◽

T Cell Subset

Abstract Long-living memory stem T cells (TSCM) with the ability to self-renew and the plasticity to differentiate into potent effectors could be valuable weapons in adoptive T-cell therapy against cancer. Nonetheless, procedures to specifically target this T-cell population remain elusive. Here, we show that it is possible to differentiate in vitro, expand, and gene modify in clinically compliant conditions CD8+ TSCM lymphocytes starting from naive precursors. Requirements for the generation of this T-cell subset, described as CD62L+CCR7+CD45RA+CD45R0+IL-7Rα+CD95+, are CD3/CD28 engagement and culture with IL-7 and IL-15. Accordingly, TSCM accumulates early after hematopoietic stem cell transplantation. The gene expression signature and functional phenotype define this population as a distinct memory T-lymphocyte subset, intermediate between naive and central memory cells. When transplanted in immunodeficient mice, gene-modified naive-derived TSCM prove superior to other memory lymphocytes for the ability to expand and differentiate into effectors able to mediate a potent xenogeneic GVHD. Furthermore, gene-modified TSCM are the only T-cell subset able to expand and mediate GVHD on serial transplantation, suggesting self-renewal capacity in a clinically relevant setting. These findings provide novel insights into the origin and requirements for TSCM generation and pave the way for their clinical rapid exploitation in adoptive cell therapy.

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Optimization of Culture Media for T Cell Expansion: T Cell Expansion Is a Bottle Neck in Adoptive T Cell Therapy

10.21203/rs.3.rs-456813/v1 ◽

2021 ◽

Author(s):

Ilnaz Rahimmanesh ◽

Hossein Khanahmad

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Cell Expansion ◽

Culture Media ◽

Adoptive Cell Therapy ◽

Interleukin 2 ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

T Cell Expansion

Abstract Adoptive T cell therapy is a promising treatment strategy for cancer immunotherapy. The methods used for the expansion of high numbers of T cells are essential steps for adoptive cell therapy. In this study, we evaluated the expansion, proliferation, activation, and anti-tumor response of T lymphocytes, in presence of different concentrations of interleukin-2, phytohemagglutinin, and insulin. Our results showed that supplemented culture media with an optimized concentration of phytohemagglutinin and interleukin-2 increased total fold expansion of T cells up to 500-fold with about 90% cell viability over 7 days. The quantitative assessment of Ki-67 in expanded T cells showed a significant elevation of this proliferation marker. In addition, the proportion of CD4+ and CD8+ cells were evaluated using flow cytometry, and data showed that both cells were present in the expanded population. Finally, we assessed the activation and tumor cytotoxicity of expanded T cells against target cells. Overexpression of CD107a, as a functional marker of T cell degranulation on expanded T cells and their ability to induce cell death in tumor cells, was observed in the co-cultured experiment. Based on these data we have developed a cost-effective and rapid method to support the efficient expansion of T cells for adoptive cell therapy.

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