scholarly journals Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma

2021 ◽  
Vol 9 (7) ◽  
pp. e002703
Author(s):  
Troels Holz Borch ◽  
Katja Harbst ◽  
Aynal Haque Rana ◽  
Rikke Andersen ◽  
Evelina Martinenaite ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitor ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Tumor Biomarker ◽  
Autologous Tumor ◽  
T Cell Therapy

PurposeDespite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this treatment. We evaluated the use of vemurafenib, a small-molecule BRAF inhibitor with immunomodulatory properties, as priming before TIL harvest and adoptive T cell therapy in a phase I/II clinical trial.Methods12 patients were treated with vemurafenib for 7 days before tumor excision and during the following weeks until TIL infusion. TILs were grown from tumor fragments, expanded in vitro and reinfused to the patient preceded by a lymphodepleting chemotherapy regimen and followed by interleukin-2 infusion. Extensive immune monitoring, tumor profiling and T cell receptor sequencing were performed.ResultsNo unexpected toxicity was observed, and treatment was well tolerated. Of 12 patients, 1 achieved a complete response, 8 achieved partial response and 3 achieved stable disease. A PR and the CR are ongoing for 23 and 43 months, respectively. In vitro anti-tumor reactivity was found in TILs from 10 patients, including all patients achieving objective response. Serum and tumor biomarker analyses indicate that baseline cytokine levels and the number of T cell clones may predict response to TIL therapy. Further, TCR sequencing suggested skewing of TCR repertoire during in vitro expansion, promoting certain low frequency clonotypes.ConclusionsPriming with vemurafenib before infusion of TILs was safe and feasible, and induced objective clinical responses in this cohort of patients with checkpoint inhibitor-resistant metastatic melanoma. In this trial, vemurafenib treatment seemed to decrease attrition and could be considered to bridge the waiting time while TILs are prepared.

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 Adoptive T-Cell Therapy Using Autologous Tumor-Infiltrating Lymphocytes for Metastatic Melanoma

2012 ◽  
Vol 18 (2) ◽  
pp. 160-175 ◽  
Author(s):  
Richard Wu ◽  
Marie-Andrée Forget ◽  
Jessica Chacon ◽  
Chantale Bernatchez ◽  
Cara Haymaker ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Adoptive T Cell Therapy ◽  
Autologous Tumor ◽  
T Cell Therapy ◽  
Infiltrating Lymphocytes

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

scholarly journals 124 Functionalizing CAR T cells for selective proliferation and dual-targeting using the meditope technology

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A133-A133
Author(s):  
Cheng-Fu Kuo ◽  
Yi-Chiu Kuo ◽  
Miso Park ◽  
Zhen Tong ◽  
Brenda Aguilar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BackgroundMeditope is a small cyclic peptide that was identified to bind to cetuximab within the Fab region. The meditope binding site can be grafted onto any Fab framework, creating a platform to uniquely and specifically target monoclonal antibodies. Here we demonstrate that the meditope binding site can be grafted onto chimeric antigen receptors (CARs) and utilized to regulate and extend CAR T cell function. We demonstrate that the platform can be used to overcome key barriers to CAR T cell therapy, including T cell exhaustion and antigen escape.MethodsMeditope-enabled CARs (meCARs) were generated by amino acid substitutions to create binding sites for meditope peptide (meP) within the Fab tumor targeting domain of the CAR. meCAR expression was validated by anti-Fc FITC or meP-Alexa 647 probes. In vitro and in vivo assays were performed and compared to standard scFv CAR T cells. For meCAR T cell proliferation and dual-targeting assays, the meditope peptide (meP) was conjugated to recombinant human IL15 fused to the CD215 sushi domain (meP-IL15:sushi) and anti-CD20 monoclonal antibody rituximab (meP-rituximab).ResultsWe generated meCAR T cells targeting HER2, CD19 and HER1/3 and demonstrate the selective specific binding of the meditope peptide along with potent meCAR T cell effector function. We next demonstrated the utility of a meP-IL15:sushi for enhancing meCAR T cell proliferation in vitro and in vivo. Proliferation and persistence of meCAR T cells was dose dependent, establishing the ability to regulate CAR T cell expansion using the meditope platform. We also demonstrate the ability to redirect meCAR T cells tumor killing using meP-antibody adaptors. As proof-of-concept, meHER2-CAR T cells were redirected to target CD20+ Raji tumors, establishing the potential of the meditope platform to alter the CAR specificity and overcome tumor heterogeneity.ConclusionsOur studies show the utility of the meCAR platform for overcoming key challenges for CAR T cell therapy by specifically regulating CAR T cell functionality. Specifically, the meP-IL15:sushi enhanced meCAR T cell persistence and proliferation following adoptive transfer in vivo and protects against T cell exhaustion. Further, meP-ritiuximab can redirect meCAR T cells to target CD20-tumors, showing the versatility of this platform to address the tumor antigen escape variants. Future studies are focused on conferring additional ‘add-on’ functionalities to meCAR T cells to potentiate the therapeutic effectiveness of CAR T cell therapy.

scholarly journals CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Lena Andersch ◽  
Josefine Radke ◽  
Anika Klaus ◽  
Silke Schwiebert ◽  
Annika Winkler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Lines ◽  
T Cell Therapy ◽  
Retinoblastoma Cell ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Background Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects. Methods CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs. Results All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing. Conclusion Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing.

scholarly journals A Review of T-Cell Related Therapy for Osteosarcoma

2020 ◽  
Vol 21 (14) ◽  
pp. 4877
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Kaoru Aoki ◽  
Jun Takahashi ◽  
Naoto Saito
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Immune Checkpoint Inhibitor ◽  
Malignant Tumors ◽  
Checkpoint Inhibitor ◽  
T Cell Response ◽  
The Other ◽  
T Cell Therapy ◽  
Tumors Of Bone ◽  
Better Than

Osteosarcoma is one of the most common primary malignant tumors of bone. The combination of chemotherapy and surgery makes the prognosis better than before, but therapy has not dramatically improved over the last three decades. This is partially because of the lack of a novel specialized drug for osteosarcoma, which is known as a tumor with heterogeneity. On the other hand, immunotherapy has been one of the most widely used strategies for many cancers over the last ten years. The therapies related to T-cell response, such as immune checkpoint inhibitor and chimeric antigen receptor T-cell therapy, are well-known options for some cancers. In this review, we offer the accumulated knowledge of T-cell-related immunotherapy for osteosarcoma, and discuss the future of the therapy.

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.

T-cell therapy in metastatic melanoma: TIL 1383I TCR transduced T cells after infusion and activity in vivo.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 3043-3043 ◽  
Author(s):  
Courtney Regan ◽  
Joseph Clark ◽  
Tamson Moore ◽  
Kelly Moxley ◽  
Gina Scurti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Metastatic Melanoma ◽  
T Cell Therapy
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