scholarly journals Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1229
Author(s):  
Ali Hosseini Rad S. M. ◽  
Joshua Colin Halpin ◽  
Mojtaba Mollaei ◽  
Samuel W. J. Smith Bell ◽  
Nattiya Hirankarn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Metabolic State ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.

Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus On Safety

2021 ◽  
Vol 16 ◽  
Author(s):  
Vikas Maharshi ◽  
Diksha Diksha ◽  
Pooja Gupta
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Background: Serious adverse reactions have been reported with the use of chimeric antigen receptor (CAR) T-cell therapy in clinical setting despite the success of these products in pre-clinical stages of development. Objective: We evaluated the quality of available pre-clinical safety data of CAR T-cell therapy products. Methods: A 21 items safety-checklist was designed specifically for CAR T-cell. Literature was searched using search/MeSH terms in PubMed (October 2019 – February 2020). Studies were screened from title and abstract. Original pre-clinical researches related to CAR T-cell anti-cancer therapy were included. Results: Of the search results, 152 studies (3 in vivo, 39 in vitro, and 110 combined) were included. Only 7.9% studies were specifically designed to evaluate/ improve product safety. Eleven studies included target antigen(s) and no study included co-stimulatory molecule(s) expressed exclusively by tumor tissue and/or CAR T-cells. One study used CRISPR-Cas9 for CAR gene insertion. The use of switch-off mechanism and purity assessment of CAR T-cell products were reported in 13.2% and 8.6% studies respectively. Of the 149 studies with in vivo component, immuno-competent animal models were used in 24.8%. Measurement of blood pressure, temperature, body weight and serum cytokines were reported in 0, 2.7, 29.2 and 27.4% studies respectively. The tissue distribution and CAR T-cells persistence were reported in 26.5% studies. Conclusion: Majority of the checklist parameters were not reported in the pre-clinical publications to be adequately predictive of the safety of CAR T-cells in a clinical setting.

scholarly journals Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1450
Author(s):  
Tahereh Soltantoyeh ◽  
Behnia Akbari ◽  
Amirali Karimi ◽  
Ghanbar Mahmoodi Chalbatani ◽  
Navid Ghahri-Saremi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Chimeric Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells. Among these, CAR T cell therapy has recently made promising strides towards the treatment of advanced hematological and solid cancers. Although CAR T cell therapy might offer new hope for melanoma patients, it is not without its shortcomings, which include off-target toxicity, and the emergence of resistance to therapy (e.g., due to antigen loss), leading to eventual relapse. The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma. We will outline specific strategies including combination approaches that could be used to overcome some limitations of CAR T cell therapy for metastatic melanoma.

scholarly journals 224 M2 macrophage-mediated immune suppression of chimeric antigen receptor T cells via PD-L1 signaling in prostate cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A238-A238
Author(s):  
Yukiko Yamaguchi ◽  
Jackson Gibson ◽  
Kevin Ou ◽  
Saul Priceman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
M2 Macrophages ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BackgroundThe immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and anti-tumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant macrophages, and infiltration of M2 macrophages correlates with metastasis and poor prognosis.MethodsTo model this in vitro, we utilized a novel co-culture system with tumor cells, prostate stem cell antigen (PSCA)-directed CAR T cells, and polarized macrophages. To investigate the TME in vivo, we took advantage of ”humanized” MISTRG mice, which are immunocompromised mice with knocked-in human genes that support human hematopoiesis and efficient tumor-infiltration of myeloid cell populations. Humanized MISTRG mice were intratibially engrafted with LAPC9 tumor cells to model bone metastatic disease.ResultsWe observed significant hampering of PSCA-CAR T cell activity in vitro with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of PD-L1 in both tumor cells and macrophages. We also observed PD-L1 expression in tumor-associated macrophages infiltrating tumors following PSCA-CAR T cell therapy in the humanized mice. Anti-PD-L1 monoclonal antibodies in combination with CAR-T cell therapy altered phenotype and survival of M2 macrophages, resulting in improved anti-tumor activity of PSCA-CAR T cells in the presence of M2 macrophages.ConclusionsRecently, immune checkpoint (IC) blockade (ICB) has been utilized in combination with chimeric antigen receptor (CAR) T cell therapy, with the notion that induction of immune responses with CAR T cells may instigate checkpoint pathways in immunologically cold tumors that would otherwise not respond to ICB. This study gives insights to a mechanism by which CAR T cells and ICB work in synergy to modulate immune landscape of immunologically cold tumors, and our ongoing studies will continue to elucidate the TME-mediated immunosuppression of CAR T cell therapy.

scholarly journals Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells

2019 ◽  
Vol 20 (6) ◽  
pp. 1283 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Clara Karches ◽  
Bruno Cadilha ◽  
Stefanie Lesch ◽  
Stefan Endres ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor’s individual components—scFv, spacer domain, and costimulatory domains—and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.

Logic-gated approaches to extend the utility of chimeric antigen receptor T-cell technology

2018 ◽  
Vol 46 (2) ◽  
pp. 391-401 ◽  
Author(s):  
Lisa M. Ebert ◽  
Wenbo Yu ◽  
Tessa Gargett ◽  
Michael P. Brown
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Tumour Antigen ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR)-T cell therapy has been clinically validated as a curative treatment for the difficult to treat malignancies of relapsed/refractory B-cell acute lymphoblastic leukaemia and lymphoma. Here, the CAR-T cells are re-directed towards a single antigen, CD19, which is recognised as a virtually ideal CAR target antigen because it has strong, uniform expression on cancer cells, and is otherwise expressed only on healthy B cells, which are ‘dispensable’. Notwithstanding the clinical success of CD19-CAR-T cell therapy, its single specificity has driven therapeutic resistance in 30% or more of cases with CD19-negative leukaemic relapses. Immune checkpoint blockade is also a highly successful cancer immunotherapeutic approach, but it will be less useful for many patients whose malignancies either lack a substantial somatic mutation load or whose tumours are intrinsically resistant. Although CAR-T cell therapy could serve this unmet medical need, it is beset by several major limitations. There is a lack of candidate antigens that would satisfy the requirements for ideal CAR targets. Biological properties such as clonal heterogeneity and micro-environmental conditions hostile to T cells are inherent to many solid tumours. Past clinical studies indicate that on-target, off-tumour toxicities of CAR-T cell therapy may severely hamper its application. Therefore, re-designing CARs to increase the number of antigen specificities recognised by CAR-T cells will broaden tumour antigen coverage, potentially overcoming tumour heterogeneity and limiting tumour antigen escape. Tuning the balance of signalling within bi-specific CAR-T cells may enable tumour targeting while sparing normal tissues, and thus minimise on-target, off-tumour toxicities.

scholarly journals Toxicities of chimeric antigen receptor T cells: recognition and management

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3321-3330 ◽  
Author(s):  
Jennifer N. Brudno ◽  
James N. Kochenderfer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy.

scholarly journals Cell Therapy for Colorectal Cancer: The Promise of Chimeric Antigen Receptor (CAR)-T Cells

2021 ◽  
Vol 22 (21) ◽  
pp. 11781
Author(s):  
Cristina Aparicio ◽  
Marina Belver ◽  
Lucía Enríquez ◽  
Francisco Espeso ◽  
Lucía Núñez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Colorectal cancer (CRC) is a global public health problem as it is the third most prevalent and the second most lethal cancer worldwide. Major efforts are underway to understand its molecular pathways as well as to define the tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) or neoantigens, in order to develop an effective treatment. Cell therapies are currently gaining importance, and more specifically chimeric antigen receptor (CAR)-T cell therapy, in which genetically modified T cells are redirected against the tumour antigen of interest. This immunotherapy has emerged as one of the most promising advances in cancer treatment, having successfully demonstrated its efficacy in haematological malignancies. However, in solid tumours, such as colon cancer, it is proving difficult to achieve the same results due to the shortage of TSAs, on-target off-tumour effects, low CAR-T cell infiltration and the immunosuppressive microenvironment. To address these challenges in CRC, new approaches are proposed, including combined therapies, the regional administration of CAR-T cells and more complex CAR structures, among others. This review comprehensively summarises the current landscape of CAR-T cell therapy in CRC from the potential tumour targets to the preclinical studies and clinical trials, as well as the limitations and future perspectives of this novel antitumour strategy.

scholarly journals Chimeric antigen receptor T cells engineered to secrete CD40 agonist antibodies enhance antitumor efficacy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yajun Zhang ◽  
Pei Wang ◽  
Tengjiao Wang ◽  
Yuan Fang ◽  
Yongmei Ding ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antitumor Efficacy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background Although chimeric antigen receptor (CAR)-T cell therapy has been remarkably successful for haematological malignancies, its efficacy against solid tumors is limited. The combination of CAR-T cell therapy with immune checkpoint inhibitors (CPIs), such as PD-1, PD-L1, and CTLA-4 antibodies, is a promising strategy for enhancing the antitumor efficacy of CAR-T cells. However, because most patients acquire resistance to CPIs, investigating other strategies is necessary to further improve the antitumor efficacy of CAR-T cell therapy for solid tumors. Recently, CD40 agonist antibodies showed potential antitumor efficacy by activating the CD40 pathway. Results Based on the piggyBac transposon system, rather than the widely used viral vectors, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possessed the ability to secrete anti-CD40 antibodies. Compared with meso3 CAR-T cells, which did not secrete the anti-CD40 antibody, meso3-CD40 CAR-T cells secreted more cytokines and had a relatively higher proportion of central memory T (TCM) cells after stimulation by the target antigen. In addition, compared with meso3 CAR-T cells, meso3-CD40 CAR-T cells had a more powerful cytotoxic effect on target cells at a relatively low effector-to-target ratio. More importantly, we demonstrated that the antitumor activity of meso3-CD40 CAR-T cells was enhanced in a human ovarian cancer xenograft model in vivo. Conclusions In conclusion, these results highlight anti-CD40-secreting CAR-T cells generated by nonviral vectors as a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

IMMU-45. COMBINATION OF EGFRVIII CAR T-CELL THERAPY AND PARACRINE GAM MODULATION FOR THE TREATMENT OF GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi103
Author(s):  
Tomás A Martins ◽  
Marie-Françoise Ritz ◽  
Tala Shekarian ◽  
Philip Schmassmann ◽  
Deniz Kaymak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Differential Expression Analysis ◽  
Dependent Manner ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract The GBM immune tumor microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). We have previously shown that blockade of CD47, a ‘don't eat me’-signal overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, monotherapy with CD47 blockade has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local CAR T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM. We generated humanized EGFRvIII CAR T-cells by lentiviral transduction of healthy donor human T-cells and engineered them to constitutively release a soluble SIRPγ-related protein (SGRP) with high affinity towards CD47. Tumor viability and CAR T-cell proliferation were assessed by timelapse imaging analysis in co-cultures with endogenous EGFRvIII-expressing BS153 cells. Tumor-induced CAR T-cell activation and degranulation were confirmed by flow cytometry. CAR T-cell secretomes were analyzed by liquid chromatography-mass spectrometry. Immunocompromised mice were orthotopically implanted with EGFRvIII+ BS153 cells and treated intratumorally with a single CAR T-cell injection. EGFRvIII and EGFRvIII-SGRP CAR T-cells killed tumor cells in a dose-dependent manner (72h-timepoint; complete cytotoxicity at effector-target ratio 1:1) compared to CD19 controls. CAR T-cells proliferated and specifically co-expressed CD25 and CD107a in the presence of tumor antigen (24h-timepoint; EGFRvIII: 59.3±3.00%, EGFRvIII-SGRP: 52.6±1.42%, CD19: 0.1±0.07%). Differential expression analysis of CAR T-cell secretomes identified SGRP from EGFRvIII-SGRP CAR T-cell supernatants (-Log10qValue/Log2fold-change= 3.84/6.15). Consistent with studies of systemic EGFRvIII CAR T-cell therapy, our data suggest that intratumoral EGFRvIII CAR T-cells were insufficient to eliminate BS153 tumors with homogeneous EGFRvIII expression in mice (Overall survival; EGFRvIII-treated: 20%, CD19-treated: 0%, n= 5 per group). Our current work focuses on the functional characterization of SGRP binding, SGRP-mediated phagocytosis, and on the development of a translational preclinical model of heterogeneous EGFRvIII expression to investigate an additive effect of CAR T-cell therapy and GAM modulation.

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