scholarly journals Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma

2020 ◽  
Vol 8 (2) ◽  
pp. e000668
Author(s):  
Troels Holz Borch ◽  
Rikke Andersen ◽  
Eva Ellebaek ◽  
Özcan Met ◽  
Marco Donia ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Adoptive T Cell Therapy ◽  
Great Promise ◽  
T Cell Therapy ◽  
Link Type

Personalized cell therapy targeting tumor antigens with expanded tumor-infiltrating lymphocytes (TILs) has shown great promise in metastatic melanoma (MM) since the 90s. However, MM was first-in line to benefit from the wave of checkpoint inhibitors (CPI), which shifted the focus of immunotherapy almost fully to immune CPI. Still, the majority of patients fail to benefit from CPI treatment, raising the intriguing question on how TIL therapy may fit into the changing landscape of melanoma treatment. We took advantage of data from a unique cohort of patients with MM treated with T-cell therapy in consecutive clinical trials at our institution across the last 10 years. Based on detailed data on patient characteristics, pre-TIL and post-TIL treatments and long-term follow-up, we were able to address the important issue of how TIL therapy can be positioned in the current CPI era. We found that previous progression on anticytotoxic T-lymphocyte-associated protein 4 do not seem to harm neither rate nor duration of response to TIL therapy. Importantly, even in the hard-to-treat population of patients who progressed on antiprogrammed cell death protein 1 (anti-PD-1), an objective response rate of 32% was achieved, including durable responses. Yet, median progression-free survival was reduced in this anti-PD-1 refractory population. Trial registration number: ClinicalTrials.gov ID: NCT00937625, NCT02379195 and NCT02354690.

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.

Adoptive T-cell therapy combined with intra-lesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20022-e20022
Author(s):  
Amir Khammari ◽  
Jean-Marc Limacher ◽  
Jean-Michel NGuyen ◽  
Melanie Saint-Jean ◽  
Gaelle Quereux ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Translational Research ◽  
Stable Disease ◽  
Objective Response ◽  
Interferon Γ ◽  
Adoptive T Cell Therapy ◽  
Surgical Biopsy ◽  
T Cell Therapy

e20022 Background: The purpose of this study was to evaluate the feasibility, safety and efficacy of adding intra-tumoral injections of TG1042 (Adenovirus 5 expressing Interferon-γ) to adoptive T cell therapy in patients with advanced stage melanoma. Methods: This was a monocentric phase I/II study. The main inclusion criteria were: stage IIIc/IV melanoma, age 18 to 75, at least one injectable metastasis. Tumor infiltrating lymphocytes (TILs) produced from a surgical biopsy of a lesion were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x1010 viral particles per lesion (in up to 6 lesions) every 2 weeks from day -15 to month 2 and then every month up to month 11 or progression. Primary objective was the safety of the procedure; secondary objectives included response according to RECIST and translational research. Results: Eighteen patients have been included. The TILs production was successful in 16 of them. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections were the most frequent adverse events observed. No grade 3 or 4 treatment related adverse events was recorded. Among the 13 patients evaluable for tumor response 4 patients (31%) had an overall objective response (2 complete, 2 partial), 1patient had a stable disease and 8 progressed. When considering only the injected lesions 6 (46%) had an objective response (3 complete, 3 partial), 3 had a stable disease and 4 progressed. Distant responses in non-injected lesions were observed for 2 patients. Translational research on cutaneous biopsies before and after injections (3 months) showed an increase of CD8 T lymphocytes, IFN-γ and STAT 1 expression in 3 patients. Conclusions: This study demonstrates that co-delivery of TILs and intra lesional TG1042 is feasible and safe. Stimulation of innate immunity by adenovirus expressing interferon-γ could contribute to reverse the immunotolerant profile of the tumour environment. These results support to further explore combined immunotherapies in the treatment of melanoma. Clinical trial information: NCT01082887.

scholarly journals Advances in the Treatment of Metastatic Melanoma: Adoptive T-Cell Therapy

2012 ◽  
Vol 39 (2) ◽  
pp. 215-226 ◽  
Author(s):  
Chantale Bernatchez ◽  
Laszlo G. Radvanyi ◽  
Patrick Hwu
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy

scholarly journals Cancer immunotherapy: current opportunities and perspectives

2021 ◽  
Vol 4 (2) ◽  
pp. 25-38
Author(s):  
O.Yu. Nikolaeva ◽  
R.V. Liubota ◽  
O.S. Zotov ◽  
R.I. Vereshchako
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Anticancer Agents ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Focus

Cancer immunotherapy is a relatively new and pro­mising method of treating neoplasms. Understanding the antigen-directed cytotoxicity of T-lymphocytes has become one of the central directions in involving the immune system in the fight against cancer. Basic research in this area has led to the invention of checkpoint inhibitors, adoptive T-cell therapy, and cancer vaccines. Cytokines can enhance the action of T-lymphocytes for their ability to directly stimulate effector and stromal cells in tumor focus and enhance recognition of tumor cells by cytotoxic effector cells. They were the first in cancer immunotherapy and remain relevant to this day. Today, immunotherapy is an effective treatment for most malignant tumors, including melanoma, non-small cell lung cancer, liver, stomach, bladder, cervical cancer, some types of breast cancer, lymphoma, etc. However, immunotherapy of some malignant tumors is ineffective, therefore, the development of new and improvement of existing immunotherapy agents is actively underway, and there is a hope that the indications for its use will expand. For this purpose, this review discusses the principles of action of various classes of immunotherapeutic anticancer agents, namely cytokines, immune checkpoint inhibitors, and adaptive T-cell therapy. The work highlights their indications, efficacy and toxicity from the use of each class of drugs, as well as the prospects for the development of immunotherapeutic anticancer drugs.

4-1BB-based Isolation and Expansion of CD8+ T Cells Specific for Self-Tumor and Non–Self-Tumor Antigens for Adoptive T-cell Therapy

2014 ◽  
Vol 37 (4) ◽  
pp. 225-236 ◽  
Author(s):  
Beom K. Choi ◽  
Sang C. Lee ◽  
Myoung J. Lee ◽  
Young H. Kim ◽  
Young-Woo Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cd8 T Cells ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy
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