scholarly journals Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Faroogh Marofi ◽  
Safa Tahmasebi ◽  
Heshu Sulaiman Rahman ◽  
Denis Kaigorodov ◽  
Alexander Markov ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Survival Rate ◽  
T Cell ◽  
Plasma Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractDespite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell’s history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells.

scholarly journals Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Faroogh Marofi ◽  
Heshu Sulaiman Rahman ◽  
Zaid Mahdi Jaber Al-Obaidi ◽  
Abduladheem Turki Jalil ◽  
Walid Kamal Abdelbasset ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
T Cell ◽  
Cancer Therapy ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractAcute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

scholarly journals Paving the Way toward Successful Multiple Myeloma Treatment: Chimeric Antigen Receptor T-Cell Therapy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 983 ◽  
Author(s):  
Ewelina Grywalska ◽  
Barbara Sosnowska-Pasiarska ◽  
Jolanta Smok-Kalwat ◽  
Marcin Pasiarski ◽  
Paulina Niedźwiedzka-Rystwej ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Side Effects ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Despite the significant progress of modern anticancer therapies, multiple myeloma (MM) is still incurable for the majority of patients. Following almost three decades of development, chimeric antigen receptor (CAR) T-cell therapy now has the opportunity to revolutionize the treatment landscape and meet the unmet clinical need. However, there are still several major hurdles to overcome. Here we discuss the recent advances of CAR T-cell therapy for MM with an emphasis on future directions and possible risks. Currently, CAR T-cell therapy for MM is at the first stage of clinical studies, and most studies have focused on CAR T cells targeting B cell maturation antigen (BCMA), but other antigens such as cluster of differentiation 138 (CD138, syndecan-1) are also being evaluated. Although this therapy is associated with side effects, such as cytokine release syndrome and neurotoxicity, and relapses have been observed, the benefit–risk balance and huge potential drive the ongoing clinical progress. To fulfill the promise of recent clinical trial success and maximize the potential of CAR T, future efforts should focus on the reduction of side effects, novel targeted antigens, combinatorial uses of different types of CAR T, and development of CAR T cells targeting more than one antigen.

scholarly journals Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

2020 ◽  
Author(s):  
Eugenia Zah ◽  
Eunwoo Nam ◽  
Vinya Bhuvan ◽  
Uyen Tran ◽  
Brenda Y. Ji ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

ABSTRACTChimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies but also demonstrated marked vulnerability to antigen escape and tumor relapse. Here, we report the rational design and systematic optimization of bispecific CAR-T cells with robust activity against multiple myeloma (MM), including heterogeneous MM that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit significantly higher CAR expression levels and greater antigen-stimulated proliferation compared to T cells that co-express individual BCMA and CS1 CARs. Compared to single-input BCMA- or CS1-targeting CAR-T cells, BCMA/CS1 bispecific CAR-T cells significantly prolong the survival of animals bearing heterogeneous MM tumors. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, but CAR-T cell treatment alone was able to achieve durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

scholarly journals Future of CAR T cells in multiple myeloma

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 272-279 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Sham Mailankody ◽  
Eric L. Smith
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Early Clinical Trial ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Despite the significant improvement in survival outcomes of multiple myeloma (MM) over the past decade, it remains an incurable disease. Patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen has transformed the treatment armamentarium of relapsed/refractory MM (RRMM), with unprecedented overall response rates in this difficult-to-treat patient population. However, a significant proportion of patients ultimately relapse despite achieving deep remission. Several innovative approaches, including alternative/dual-antigen–specific CAR T-cell constructs, genetically engineered “off-the-shelf” CAR T cells, and strategies to counteract an immunosuppressive microenvironment, may dramatically reshape the field of CAR T-cell therapy in the future. These strategies are being actively investigated in preclinical and early clinical trial settings with the hopes of enhancing the durability of responses and, thereby, improving the overall survival of RRMM patients after CAR T-cell therapy.

scholarly journals Perspectives for the Use of CAR-T Cells for the Treatment of Multiple Myeloma

2021 ◽  
Vol 12 ◽  
Author(s):  
Marcin Jasiński ◽  
Grzegorz W. Basak ◽  
Wiesław W. Jedrzejczak
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Advantages And Disadvantages ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

During recent years considerable progress has been made in the treatment of multiple myeloma. However, despite the current improvements in the prognosis of this malignancy, it always ends with relapse, and therefore new therapy approaches for destroying resistant cancer cells are needed. Presently, there is great hope being placed in the use of immunotherapy against refractory/relapsed multiple myeloma which is unresponsive to any other currently known drugs. The most promising one is CAR-T cell therapy which has already shown tremendous success in treating other malignancies such as acute lymphoblastic leukaemia (ALL) and could potentially be administered to multiple myeloma patients. CAR-T cells equipped with receptors against BCMA (B-cell maturation antigen), which is a surface antigen that is highly expressed on malignant cells, are now of great interest in this field with significant results in clinical trials. Furthermore, CAR-T cells with other receptors and combinations of different strategies are being intensively studied. However, even with CAR-T cell therapy, the majority of patients eventually relapse, which is the greatest limitation of this therapy. Serious adverse events such as cytokine release syndrome or neurotoxicity should also be considered as possible side effects of CAR-T cell therapy. Here, we discuss the results of CAR-T cell therapy in the treatment of multiple myeloma, where we describe its main advantages and disadvantages. Additionally, we also describe the current results that have been obtained on using combinations of CAR-T cell therapies with other drugs for the treatment of multiple myeloma.

scholarly journals A Bispecific CAR-T Cell Therapy Targeting Bcma and CD38 for Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase 1 Dose-Climbing Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 930-930 ◽  
Author(s):  
Chenggong Li ◽  
Heng Mei ◽  
Yu Hu ◽  
Tao Guo ◽  
Lin Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Phase 1 ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Background: Anti-B cell maturation antigen (BCMA) chimeric antigen receptor(CAR) T cell therapy has shown promising results from a series of clinical trials. But short progression-free survival (PFS) due to BCMA-negative or positive relapse is pretty much the agenda.Here we constructed a dual-target BM38 CAR incorporating the anti-CD38 and anti-BCMA single-chain variable fragment in tandem plus 4-1BB signaling and CD3 zeta domains and conducted the first-in-human clinical trial(ChiCTR1800018143) in patients with RRMM to evaluate the safety, efficacy and duration of BM38 T cells. Methods:Patients with relapsed or refractory multiple myeloma(RRMM), who had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, were enrolled in the phase 1 dose-climbing trial of the bispecific CAR-T cell therapy. Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2, d-5 to d-3) and Flu(25 mg/m2, d-5 to d-3) daily prior to the CAR-T infusion (d0). The dose gradients of infused CAR-T cells were 0.5, 1.0, 2.0, 3.0 and 4.0×106 cells/kg and at least 2 patients were involved at every dose level. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma (2016), and the toxicity was graded by CTCAE 5.0. Results: As of 31 July 2019, 16 pts consisting of 10(62.5%) with genetic abnormalities and 5(31.25%) with extramedullary lesions,had received BM38 CAR-T cells in the 5 dose-climbing cohorts. At a median follow-up of 36 weeks, no DLTs and no grade ≥ 3 neurotoxicities were observed. Cytokine release syndrome (CRS), mainly grade 1-2, was reported in 10 of 16 (62.5%) pts; 4 pts had grade ≥ 3 CRS that resolved by tocilizumab and supportive treatment. Almost all the pts were observed with hematological toxicities relieved in the first month after infusion.14(87.5%) pts achieved an overall response with 8(50%) sCR, 2(12.5%) VGPR and 4(25.00%) PR and 14(87.5%) reached bone marrow minimal residual disease(MRD)-negative status. The longest duration of sCR was over 51 weeks and 5(62.5%) of 8 patients had still maintained sCR and 2 transformed to VGPR and 1 to PR. The median duration of progression-free survival(PFS) had not been reached; PFS rates at 9 months was 75%. More encouragingly, 5(100%)extramedullary lesions were eliminated.Up to the observed day, the BM38 CAR-T cells still exist in the patients' peripheral blood by flow cytometry(FCM) and quantitative polymerase chain reaction(q-PCR). The peak time of CAR-T cells proliferation of sCR patients was about the 2nd week after infusion, which was earlier than other patients. 4.0 × 106 CAR T cells (pt11, 12 and 15) were selected for the optimal dose with superior response and acceptable toxicities and expansion cohort would be conducted. Conclusions:Our study demonstrates an improved efficacy with the bivalent BM38 CAR-T therapy for RRMM with a high ORR, especially a higher rate and a longer duration of sCR and effective elimination for extramedullary lesions. No neurotoxicity was observed. CRS and other toxicities were manageable. These initial data provide strong evidence to support the further development of the dual-target CAR-T therapy for RRMM. Clinical trial information: ChiCTR1800018143 Disclosures No relevant conflicts of interest to declare.

scholarly journals A Preliminary Study on the Safety and Efficacy of a Novel Human BCMA-Targeting CAR-T Therapy in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1735-1735
Author(s):  
Yi Wang ◽  
Ying Gao ◽  
Hui Wang ◽  
Ding Zhang ◽  
Yan Zheng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Plasma Cells ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Safety And Efficacy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Introduction Multiple myeloma is a hematological malignancy that is prone to be companied by bone marrow destruction, renal impairment and extramedullary infiltration. Current treatments include proteasome inhibitor, immunomodulatory drug, hematopoietic stem cell transplantation, and monoclonal antibody targeted therapies. However, it is still clinically incurable. Chimeric antigen receptor (CAR) T-cell therapy is a new immune targeted therapeutic strategy. It is reported better clinical efficacy for relapsed/refractory multiple myeloma (r/r MM) treatment has been achieved by immunotherapies targeted B-cell maturation antigen (BCMA). Therefore, it is important to investigate the treatment of a novel human BCMA-specific CAR-T therapy for r/r MM. Objective The objective of this clinical study is to evaluate the safety and efficacy of the novel human BCMA-targeting CAR-T therapy in patients with r/r MM, especially patients who relapsed from prior CAR-T therapy. Method This work is a clinical study registered and investigated by our center. CD3+ T cells were negatively selected from patients' peripheral blood mononuclear cells, activated and modified by lentivirus to produce anti-BCMA CAR-T cells. The cells were administrated intravenously to patients after expanding for 7-13 days in vitro. 24 patients had enrolled in this study, with 13 males and 11 females. The median age was 53 years old (range,41-75), and patients with cytogenetically high risk factors accounting for 41.66% (10/24). 50% (12/24) was infiltrated with extramedullary lesions. 16.6% (4/24) of them had relapsed from other CAR-T therapies before this enrollment. 50% (12/24) had been previously conducted autologous hematopoietic stem cell transplantation (HSCT), whereas 4.16% (1/24) with allogeneic HSCT. Patients with the expression of BCMA in the plasma cells higher than 30%, accounted for 25% (6/24). 2-3 days after being administered the lymphodepleting chemotherapy regimen, CAR-T cells were infused intravenously. The indicators of patients' condition were detected, including inflammatory cytokine concentration, serum protein levels, CAR-T cell number copies, and the proportion of plasma cells by bone marrow biopsy. The improvement of patients, the occurrence of adverse reactions, the incidence and grade of cytokine release syndrome (CRS), was analyzed and evaluated. Result All patients received infusions of CAR-T positive cells at the average dose of 9.45×10 6/kg (5-17.5) and the median injection day is the 10th day (8th-13th day) after cell isolation. After infusion, 100% (24/24) of the patients had fever lasting for 48 hours, with 37.5% (9/24) of them showing low blood pressure and being treated with drug. Heart rate increase was found in 45.8% (11/24). Nausea, diarrhea and transient consciousness disorder occurred in 50% (12/24), 33.3% (8/24), and 12.5% (3/24) of them, respectively. 16.6% (4/24) was administrated with dexamethasone to relieve symptoms, with the total dose less than 20 mg, while nobody was treated with IL-6 receptor antagonist. CAR-T cells had expanded in all patients, reaching the peak at the 4th day after infusion (Figure). The levels of IL-6, IL-8 and IFN-γ in peripheral blood also increased significantly. The incidence of CRS is 100%, of which grade I, II and III is 62.5%, 33.3% and 4.2%, respectively. 2 patients showed grade I CRES, constituting 8.3% (2/24). All patients were assessed for the efficacy of CAR-T cells 2 weeks after infusion. ORR was 100%, with 4.2% (1/24) MR, 8.3% (2/24) PR, 62.5% (15/24) VGPR and 25% (6/24) CR. 18 patients were treated for more than 1 month, with 11.1% (2/18) PR, 44.4% (8/18) VGPR, 11.1% (2/18) CR, and 33.3% (6/18) sCR. 16 patients were infused before more than 2 months, with 25% (4/16) VGPR, 12.5% (2/16) CR, 50% (8/16) sCR, and 12.5% (2/16) PD. 6 patents were administrated more than 3 months ago, with 1 developing deep remission to sCR from VGPR. The others remain the same condition. Conclusion The novel human BCMA targeted CAR-T cell therapy of this study showed safety and efficacy in the treatment of r/r MM patients with extramedullary infiltration, high-risk cytogenetical factors as well as relapse with prior BCMA CAR exposures. Deep remission can be achieved. However, more observation need to be conducted. The CAR-T treatment of BCMA target still cannot prevent the disease progress of a small numbers of patients. The control after CAR-T therapy needs more investigation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2639
Author(s):  
Massimo Martino ◽  
Filippo Antonio Canale ◽  
Caterina Alati ◽  
Iolanda Donatella Vincelli ◽  
Tiziana Moscato ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Recent Advances ◽  
Car T Cell Therapy ◽  
Car T

Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise.

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.

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.

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