A Phase I Study of Allogeneic Ex Vivo Expanded Gamma Delta (γδ) T Cells in Combination With Dinutuximab, Temozolomide, Irinotecan, and Zoledronate in Children With Refractory/ Relapsed, or Progressive Neuroblastoma or Refractory/ Relapsed Osteosarcoma

The goal of this clinical trial is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate in children with refractory or recurrent neuroblastoma or refractory/ relapsed osteosarcoma as well as to define the toxicities of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate

Start Date06 Nov 2023

Sponsor / Collaborator

Emory University

JPRN-UMIN000015233 / CompletedPhase 1/2IIT

Intraperitoneal injection of in vitro expanded Gamma Delta T cells together with zoledronate for the treatment of malignant ascites to ovarian cancer ; to evaluate the safety and efficacy. (A Phase 1/2a study) - Intraperitoneal injection of in vitro expanded Gamma Delta T cells together with zoledronate for the treatment of malignant ascites to ovarian cancer ; to evaluate the safety and efficacy. (A Phase 1/2a study)

Start Date24 Sep 2014

Sponsor / Collaborator-

100 Clinical Results associated with γδ T cells(Emory University)

100 Translational Medicine associated with γδ T cells(Emory University)

100 Patents (Medical) associated with γδ T cells(Emory University)

Literatures (Medical) associated with γδ T cells(Emory University)

01 Feb 2023·Cancer Immunology, Immunotherapy

CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?

Review

Author: Sakshi, Seth ; Ganapathy, Thamizhselvi ; Radhakrishnan, Rajalingam ; Martin, Sunil

Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although αβ T cells are time-tested chassis for CAR, potential graft versus host disease (GvHD) apart from cytokine toxicity and antigen escape pose limitations to this approach. αβ T cell malignancy challenges isolation and expansion of therapeutic T cells. Moreover, αβ T cells may pose toxicity risk to inflammation sensitive vital tissues bearing the tumor. The HLA independent, multivalent, versatile and systemic anti-tumor immunity increases the desirability of γδ T cells as an alternate chassis for CAR. Indeed, CD19 γδ CAR T cell therapy to treat advanced lymphoma reached a milestone with the fast track status by FDA. However, reduced tumor-toxicity, homing, in vivo persistence and heterogeneity limits the translation of this therapy. The field is gaining momentum in recent years with optimization of gene delivery approaches and mechanistic insights into co-signaling requirements in γδ T cells. There is a renewed interest in customizing design of CAR guided by the biology of the host immune cells. Progress has been made in the current good manufacturing practice compatible expansion and engineering protocols for the δ1 and δ2 T cells. γδ CAR T cells may find its niche in the clinical situations wherein conventional CAR therapy is less suitable due to propensity for cytokine toxicity or off-tumor effect. As the therapy is moving towards clinical trials, this review chronicles the hitherto progress in the therapeutic engineering of γδ T cells for cancer immunotherapy.

Frontiers in ImmunologyQ2 · MEDICINE

Clinical Applications of Gamma Delta T Cells with Multivalent Immunity

Q2 · MEDICINE

ReviewOA

Author: Moyes, Judy S ; Deniger, Drew C ; Cooper, Laurence J N

γδ T cells hold promise for adoptive immunotherapy because of their reactivity to bacteria, viruses, and tumors. However, these cells represent a small fraction (1-5%) of the peripheral T-cell pool and require activation and propagation to achieve clinical benefit. Aminobisphosphonates specifically expand the Vγ9Vδ2 subset of γδ T cells and have been used in clinical trials of cancer where objective responses were detected. The Vγ9Vδ2 T cell receptor (TCR) heterodimer binds multiple ligands and results in a multivalent attack by a monoclonal T cell population. Alternatively, populations of γδ T cells with oligoclonal or polyclonal TCR repertoire could be infused for broad-range specificity. However, this goal has been restricted by a lack of applicable expansion protocols for non-Vγ9Vδ2 cells. Recent advances using immobilized antigens, agonistic monoclonal antibodies (mAbs), tumor-derived artificial antigen presenting cells (aAPC), or combinations of activating mAbs and aAPC have been successful in expanding gamma delta T cells with oligoclonal or polyclonal TCR repertoires. Immobilized major histocompatibility complex Class-I chain-related A was a stimulus for γδ T cells expressing TCRδ1 isotypes, and plate-bound activating antibodies have expanded Vδ1 and Vδ2 cells ex vivo. Clinically sufficient quantities of TCRδ1, TCRδ2, and TCRδ1(neg)TCRδ2(neg) have been produced following co-culture on aAPC, and these subsets displayed differences in memory phenotype and reactivity to tumors in vitro and in vivo. Gamma delta T cells are also amenable to genetic modification as evidenced by introduction of αβ TCRs, chimeric antigen receptors, and drug-resistance genes. This represents a promising future for the clinical application of oligoclonal or polyclonal γδ T cells in autologous and allogeneic settings that builds on current trials testing the safety and efficacy of Vγ9Vδ2 T cells.

Oncology LettersQ4 · MEDICINE

Therapeutic effect of targeted Fas-expressing adenoviruses method combining γδ T cells in a mouse model of human ovarian carcinoma

Q4 · MEDICINE

Article

Author: Jiang, Fuyan ; Sheng, Shuting ; He, Hongying ; Lin, Jiajing ; Lan, Ying ; Tan, Guangping ; Zeng, Dingyuan

The present study aimed to investigate the therapeutic effect and safety of targeted use of Fas-expressing adenoviruses combined with γδ T cell-mediated killing to treat human ovarian cancer xenografts in BALB/c mice. Shuttle plasmids containing control elements of human telomerase reverse transcriptase promoter and two-step transcriptional amplification system were constructed and packaged into adenovirus-5 vectors to generate expression of an exogenous Fas gene. A mouse xenograft model of human ovarian carcinoma was constructed. A total of 35 BALB/c mice were randomly divided into five groups, which were injected with PBS, γδ T cells, Fas-expressing adenoviruses, taxol, or Fas-expressing adenovirus and γδ T cells. The weight and volume of tumors in mice in each group was monitored. Tissue sections of the various tissues of mice in the Fas-expressing adenovirus and γδ T cells group was compared with those in the PBS group to evaluate the safety of Fas-expressing adenovirus and γδ T cells in the treatment of human ovarian cancer xenograft tumors. The results of the present study indicated that mice in all treatment groups were alive at the end of the treatment course. Tumor weight and volume was the highest in the PBS group, followed successively by the adenovirus group, the γδ T cell group, the adenovirus and γδ T cell group, and the taxol group. The weight and volume inhibition rate in adenovirus and γδ T cell group were significantly higher compared with in the PBS group (P<0.05). Pathological observation of tissue samples revealed that none of vital organs in the adenovirus and γδ T cell group developed any evident morphological changes during treatment, when compared with healthy controls. In conclusion, the combined therapy with Fas-expressing adenoviruses and γδ T cells is efficient and safe for the treatment of mouse human ovarian carcinoma xenografts.

News (Medical) associated with γδ T cells(Emory University)

04 May 2023

·www.sciencedaily.com

Gamma delta T cells can fight aggressive breast cancer

Researchers discover a mechanism by which cancer cells escape the immune system. Triple-negative breast cancer (TNBC) is the most aggressive and deadly form of breast cancer with limited treatment options and a high probability of recurrence. Tumor growth and relapse of TNBC are driven by breast cancer stem cells, and improved therapies that can eliminate those hardy cells are urgently needed. Researchers from the University of Frieburg discovered that coordinated differentiation and changes in the metabolism of breast cancer stem cells make them invisible for the immune system. Counteracting the metabolic change with the drug zolendronate could make immunotherapy using gamma delta T cells more efficient against TNBC. The research team was led by Prof. Dr. Susana Minguet from the Cluster of Excellence CIBSS -- Centre for Integrative Biological Signalling Studies at the University of Freiburg, in collaboration with Dr. Jochen Maurer from the University Hospital RWTH Aachen, Dr. Mahima Swamy from the Universtiy of Dundee/Scotland and collaborators from the University Hospital Freiburg. The study was published in the Journal Cancer Immunology Research, a journal of the American Association for Cancer Research. TNBC cells hide from gamma delta T cells Gamma delta T cells recognize and kill cells that produce stress-induced molecules and phosphoantigens, a common characteristic of cancer cells. Because gamma delta T cells work differently to other types of T cells, they are being investigated as an alternative to existing immunotherapies. In the current study, the researchers tested the effect of gamma delta T cells on TNBC using isolated cancer cells and a recently developed mouse model that closely replicates the tumor properties found in human patients. While the gamma delta T cells worked well against isolated breast cancer stem cells from patients, they had a much weaker effect in the mouse model. This was due to adaptations of the cancer cells that let them stay unnoticed by the immune system, the researchers found. These adaptations included the downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens -- one of the classes of molecules that gamma T cells recognize. This escape mechanism likely also happens in patients with TNBC: analysis of public patient databases showed that reduced expression of key molecules of the mevalonate pathway correlate with a worse prognosis. The immune evasion of TNBC cells is reversible This newly discovered escape mechanism can be counteracted by the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastasis. When the researchers treated the escapist cells with zolendronate, the gamma T cells became a lot more efficient in clearing the cancer. "Our findings explain why current clinical trials using gamma delta T cells are not resulting in the expected success," Minguet summarizes. "We found a possible pharmacological-based approach to revert immune escape, which paves the way for novel combinatorial immunotherapies for triple negative breast cancer."

ImmunotherapyDrug Approval

17 Jan 2023

·www.biospace.com

TC BioPharm Announces Strategic Collaboration to Advance Gamma Delta T Cells in Oncology

Endeavor to focus on expanding understanding of gamma-delta T cells in oncological settings EDINBURGH, Scotland, Jan. 17, 2023 /PRNewswire/ -- TC BioPharm (Holdings) PLC ("TC Biopharm" or the "Company") (NASDAQ: TCBP) (NASDAQ: TCBPW), a clinical stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer treatment, today announces a strategic collaboration with The MD Anderson Cancer Center to expand the knowledge base of how gamma-delta T cells work in oncology settings. The collaboration brings together MD Anderson's clinical trial infrastructure and the translational research expertise of its immunotherapy platform with the clinical data of TC BioPharm's targeted gamma-delta T cell oncology pipeline. Under the terms of the three-year agreement, the research teams will work together on both preclinical and clinical studies to evaluate the potential for gamma-delta T cell therapies and to better understand the behaviors of these cells in patients. The collaborators will form a six-person steering committee to drive the development of both the data set and subsequent assays for each study. The comprehensive immunoprofiling capabilities of MD Anderson's immunotherapy platform will enable correlative studies on clinical samples to uncover detailed insights on the behavior of gamma-delta T cells and corresponding responses in patients. The platform is co-led by Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology, and James Allison, Ph.D., regental chair of Immunology. Formulating a better picture of what is occurring in patients during gamma delta T cell therapies is expected to allow TC Biopharm to better design future studies as well as form a view towards future targeted cancer studies in other blood cancers and solid tumors potentially. "We are enthusiastic about working with MD Anderson to further our knowledge of gamma delta T cells in order to help TC Biopharm develop future trials and treatments using our platform therapy OmnImmune," said Bryan Kobel, CEO of TC BioPharm. "This collaboration reinforces our mutual commitment to accelerating the discovery and development of cell therapies, and it highlights TC Biopharm's expertise in the gamma delta T cell space." About TC BioPharm (Holdings) PLC TC BioPharm is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of gamma-delta T cell therapies for the treatment of cancer with human efficacy data in acute myeloid leukemia. Gamma-delta T cells are naturally occurring immune cells that embody properties of both the innate and adaptive immune systems and can intrinsically differentiate between healthy and diseased tissue. TC BioPharm uses an allogeneic approach in both unmodified and CAR modified gamma-delta T cells to effectively identify, target and eradicate both liquid and solid tumors in cancer. TC BioPharm is the leader in developing gamma-delta T cell therapies, and the first company to conduct phase II/pivotal clinical studies in oncology. The Company is conducting two investigator-initiated clinical trials for its unmodified gamma-delta T cell product line - Phase 2b/3 pivotal trial for OmnImmune® in treatment of acute myeloid leukemia using the Company's proprietary allogenic CryoTC technology to provide frozen product to clinics worldwide. TC BioPharm also maintains a robust pipeline for future indications in solid tumors and a significant IP/patent portfolio in the use of CARs with gamma-delta T cells and owns our manufacturing facility to maintain cost and product quality controls. Forward Looking Statements This press release may contain statements of a forward-looking nature relating to future events. These forward-looking statements are subject to the inherent uncertainties in predicting future results and conditions. These statements reflect our current beliefs, and a number of important factors could cause actual results to differ materially from those expressed in this press release. We undertake no obligation to revise or update any forward-looking statements, whether as a result of new information, future events or otherwise. The reference to the website of TC BioPharm has been provided as a convenience, and the information contained on such website is not incorporated by reference into this press release. Company Codes: NASDAQ-NMS:TCBP

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