scholarly journals Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic

2021 ◽  
Vol 118 (26) ◽  
pp. e2025930118
Author(s):  
Iñaki Etxeberria ◽  
Elixabet Bolaños ◽  
Alvaro Teijeira ◽  
Saray Garasa ◽  
Alba Yanguas ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Adoptive T Cell Therapy ◽  
Antitumor Efficacy ◽  
Liver Inflammation ◽  
Antigen Binding Site ◽  
Antitumor Effects ◽  
T Cell Therapy ◽  
Preferential Cleavage ◽  
Regional Lymphadenectomy ◽  
Reduced Toxicity

Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation–related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment. This construct, which encompasses a protease-cleavable linker holding in place a peptide that masks the antigen binding site, exerted antitumor effects comparable to the unmodified antibody but did not result in liver inflammation. Moreover, it efficaciously synergized with both PD-1 blockade and adoptive T-cell therapy. Surprisingly, minimal active Pb-Tx reached tumor-draining lymph nodes, and regional lymphadenectomy did not abrogate antitumor efficacy. By contrast, S1P receptor–dependent recirculation of T cells was absolutely required for efficacy. The preferential cleavage of the anti-CD137 Pb-Tx by tumor proteases offers multiple therapeutic opportunities, including neoadjuvant therapy, as shown by experiments in which the Pb-Tx is given prior to surgery to avoid spontaneous metastases.

scholarly journals In situ thermal ablation augments antitumor efficacy of adoptive T cell therapy

2019 ◽  
Vol 36 (sup1) ◽  
pp. 22-36 ◽  
Author(s):  
Fumito Ito ◽  
Trupti D. Vardam ◽  
Michelle M. Appenheimer ◽  
Kevin H. Eng ◽  
Sandra O. Gollnick ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Thermal Ablation ◽  
Adoptive T Cell Therapy ◽  
Antitumor Efficacy ◽  
T Cell Therapy

Effect of modulation of the hostile tumor microenvironment through adoptive transfer of IL-12 expressing MUC-16 targeted T cells on ovarian tumors in vivo.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2586-2586
Author(s):  
Alena A. Chekmasova ◽  
Samith Sandadi ◽  
David R. Spriggs ◽  
Renier J. Brentjens
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Model ◽  
Retroviral Vectors ◽  
Ovarian Tumors ◽  
Adoptive T Cell Therapy ◽  
Antitumor Efficacy ◽  
Ovarian Carcinomas ◽  
T Cell Therapy

2586 Background: T cells may be genetically modified to recognize tumor associated antigens (TAAs) through the introduction of genes encoding artificial T cell receptors termed chimeric antigen receptors (CARs). MUC16 (CA125) is an antigen over-expressed on ovarian carcinomas and a serum marker for the diagnosis of ovarian cancer. We have previously demonstrated enhanced antitumor efficacy of CAR+ T cells further modified to secrete IL-12. We therefore tested whether MUC-16 targeted T cells further modified to express IL-12 would exhibit an enhanced antitumor efficacy in a syngeneic immunocompetent tumor model of ovarian cancer. Methods: We have constructed SFG retroviral vectors encoding the second (4H11m28mz) generation CARs as well as IL-12 modified CAR (4H11m28mz/mIL12) targeted to the retained extra-cellular domain of MUC16, termed MUC-CD. We demonstrated an antitumor efficacy of these T cells in a syngeneic tumor model using the C57BL6 (B6) mice intraperitoneally (i.p.) injected with ID8(MUC-CD) tumor cells. Results: In our studies treatment of mice bearing established ID8(MUC-CD) ovarian tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T cells targeted to MUC-CD alone, fully eradicate highly advanced intraperitoneal ovarian tumors. Significantly, we found that mice treated with 4H11m28mz/mIL12 T cells had increased number of modified T cells in the peritoneum at day 4 and 7 with increased recruitment of endogenous T cells to the site of the tumor when compared to controls and mice treated with 4H11m28mz T cells. The observed antitumor effect did not required prior lymphodepletion and was well tolerated in treated mice. Conclusions: CAR modified T cells targeted to the MUC-16 antigen efficiently eradicate orthotopic ovarian cancer in syngeneic immunocompetent mice with markedly enhanced antitumor efficacy seen in those mice treated with CAR+ T cells further modified to secrete IL-12. These data support future clinical trials utilizing adoptive T cell therapy in patients with relapsed ovarian cancer.

scholarly journals 'Off-the-shelf’ allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies

2021 ◽  
Vol 9 (2) ◽  
pp. e001608
Author(s):  
Debottam Sinha ◽  
Sriganesh Srihari ◽  
Kirrliee Beckett ◽  
Laetitia Le Texier ◽  
Matthew Solomon ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Adoptive T Cell Therapy ◽  
Nuclear Antigen ◽  
T Cell Therapy ◽  
In Vivo Models ◽  
Hla Alleles ◽  
Cell Therapies ◽  
Wide Range

BackgroundEpstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic ‘off-the-shelf’ virus-specific T-cell therapies for post-transplant viral complications.MethodsTaking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies.ResultsThese allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a ‘restriction-switching’ approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy.ConclusionThese findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

2015 ◽  
Vol 26 (5) ◽  
pp. 276-285 ◽  
Author(s):  
David Edward Gilham ◽  
John Anderson ◽  
John Stephen Bridgeman ◽  
Robert Edward Hawkins ◽  
Mark Adrian Exley ◽  
...  
Keyword(s):  
United Kingdom ◽  
T Cell ◽  
Cell Therapy ◽  
Annual Meeting ◽  
Adoptive T Cell Therapy ◽  
British Society ◽  
T Cell Therapy ◽  
The United Kingdom ◽  
Gene And Cell Therapy
Sign in / Sign up

Export Citation Format

Share Document