scholarly journals Clonal hematopoiesis in patients receiving chimeric antigen receptor T-cell therapy

2021 ◽  
Vol 5 (15) ◽  
pp. 2982-2986
Author(s):  
Peter G. Miller ◽  
Adam S. Sperling ◽  
Elliott J. Brea ◽  
Mark B. Leick ◽  
Geoffrey G. Fell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Clinical Outcomes ◽  
Chimeric Antigen Receptor ◽  
Autologous Transplantation ◽  
T Cell Therapy ◽  
Clonal Hematopoiesis ◽  
Car T Cells ◽  
Car T

Abstract Chimeric antigen receptor (CAR) T-cells have emerged as an efficacious modality in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP), a state in which mutations in hematopoietic cells give rise to a clonal population of cells, is more common in patients exposed to cytotoxic therapies, has been shown to influence inflammatory immune programs, and is associated with an adverse prognosis in patients with NHL and MM receiving autologous transplantation. We therefore hypothesized that CHIP could influence clinical outcomes in patients receiving CAR T-cell therapy. In a cohort of 154 patients with NHL or MM receiving CAR T-cells, we found that CHIP was present in 48% of patients and associated with increased rates of complete response and cytokine release syndrome severity, but only in patients younger than age 60 years. Despite these differences, CHIP was not associated with a difference in progression-free or overall survival, regardless of age. Our data suggest that CHIP can influence CAR T-cell biology and clinical outcomes, but, in contrast to autologous transplantation, CHIP was not associated with worse survival and should not be a reason to exclude individuals from receiving this potentially life-prolonging treatment.

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.

scholarly journals Profile of Capillary-Leak Syndrome in Patients Received Chimeric Antigen Receptor T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5204-5204 ◽  
Author(s):  
Yongxian Hu ◽  
Jingjing Feng ◽  
Mi Shao ◽  
He Huang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Capillary Leak Syndrome ◽  
Capillary Leak ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Abstract Background: Autologous T cells modified to express a chimeric antigen receptor (CAR-T) has demonstrated exciting efficacy in treating leukemia and there has been some reports about the toxicities recently. However, the spectrum of capillary-leak syndrome (CLS) associated with CAR-T cell therapy has not been systematically evaluated, which can be a life threatening complication as results of the cytokine release syndrome (CRS). Therefore, as the use of CAR-T therapy continues to expand to broader applications, it is prudent to characterize the profile of CLS to help providers guide safe management. Method: We reviewed all acute lymphoblastic leukemia (ALL) patients who had participated in the clinical trial from our center to receive CAR-T therapy between 2016-2018. Patients analyzed in the study received either CD19 CAR-T cells or CD19 plus CD22 CAR-T cells. The diagnosis of CLS includes edema, acute hypotension and hemoconcentration with hypoproteinemia or hypoalbuminemia. CRS grading was evaluated with Lee's criteria for CRS. Result: 42 ALL patients were included in this study with the mean age of 27(8-52) years old. 11(11/42, 26.2%) patients were diagnosed as CLS and 31 were not. It was observed that CLS was more common in patients who developed severe CRS. Patients with CLS was found to have high rate of hypotension and use of gamma globulin.(Table 1) Top level concentration of serum IL-6 in CLS patients was much higher than that in non-CLS patients (16438.7 vs 3292.7 pg/mL, p=0.0016), which is consistent with the well recognized concept of IL-6 as an indicator of CRS.(Figure 1) It is important to notice that CLS patients had lower levels of serum total protein (TP, 43.7 vs 52.8 g/L, p=0.0005) and serum albumin (ALB, 27.4 vs 33.8 g/L, p=0.0011), while the hemoglobin (HGB) concentration showed no difference, suggesting that TP and ALB might be better indicators for CLS than HGB, although hemoconcentration, hypoproteinemia and hypoalbuminemia are both important in diagnosis.(Figure 2) Moreover, there was no significant difference in age, gender, Ph type of ALL, type of CAR-T cells infused and death ratio.(Table 1) Although CRS has been reported to be related with disease burden before the therapy, our data showed no difference of it between the patients with and without CLS. Conclusion: In conclusion, we have evaluated a basic profile of CLS among CAR-T patients in our center and the study indicates that CLS warrants extra attention for patients who receive CAR-T therapy. Further investigations are required to elucidate best practices for prevention and management of CLS in CAR-T therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy

2021 ◽  
Vol 288 (1947) ◽  
Author(s):  
Gregory J. Kimmel ◽  
Frederick L. Locke ◽  
Philipp M. Altrock
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.

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 T-Cell Therapy for Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2024 ◽  
Author(s):  
Naoki Hosen
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T

CD19 Chimeric antigen receptor (CAR) T cell therapy has been shown to be effective for B cell leukemia and lymphoma. Many researchers are now trying to develop CAR T cells for various types of cancer. For multiple myeloma (MM), B-cell maturation antigen (BCMA) has been recently proved to be a promising target. However, cure of MM is still difficult, and several other targets, for example immunoglobulin kappa chain, SLAM Family Member 7 (SLAMF7), or G-protein coupled receptor family C group 5 member D (GPRC5D), are being tested as targets for CAR T cells. We also reported that the activated integrin β7 can serve as a specific target for CAR T cells against MM, and are preparing a clinical trial. In this review, we summarized current status of CAR T cell therapy for MM and discussed about the future perspectives.

scholarly journals Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 191 ◽  
Author(s):  
Benjamin Heyman ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Current Status ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor T cells (CAR T Cells) have led to dramatic improvements in the survival of cancer patients, most notably those with hematologic malignancies. Early phase clinical trials in patients with solid tumors have demonstrated them to be feasible, but unfortunately has yielded limited efficacy for various cancer types. In this article we will review the background on CAR T cells for the treatment of solid tumors, focusing on the unique obstacles that solid tumors present for the development of adoptive T cell therapy, and the novel approaches currently under development to overcome these hurdles.

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 Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2523
Author(s):  
Robert J. Cronk ◽  
Joanna Zurko ◽  
Nirav N. Shah
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy and response durability. Despite excellent initial response rates with single antigen targeting CARs, failure to respond to therapy and relapse due to target antigen downregulation remain clinical challenges. To mitigate immunophenotypic selective pressures, simultaneous dual antigen targeting with bispecific CAR T cells or multiple administration of different populations of CAR T cells may prevent relapse by addressing one resistance mechanism attributed to antigenic loss. This article will review recently published data on the use of dual targeting with CAR T cells from early phase clinical trials aimed at treating B cell malignancies and multiple myeloma.

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 Clinical Study on the CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Acute Lymphoblast Leukemia: A Single Center of Real World Data

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4834-4834
Author(s):  
Jing Huang ◽  
Zhi Liu ◽  
Ruiming Ou ◽  
Liling Zheng ◽  
Yangmin Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Acute Lymphoblast Leukemia

Abstract Objective To evaluate the efficacy and safety of the CD19-targeted chimeric antigen receptor T-cell(CD19-CAR-T) therapy for relapsed/refractory B-cell acute lymphoblast leukemia(B-ALL). Methods The efficacy and safety of CD19-CAR-T cells(4-1BB costimulatory domain) in treatment of 34 patients with relapsed/refractory B-ALL from March 2015 to December 2019 in the Department of Hematology of Guangdong Second Province Hospital were collected analyzed retrospectively. There were 18 cases (52.9%) with high-risk cytogenetic or molecular markers, 14 cases (41.2%) with tumor load was ≥50% before transfusion, 24 cases (70.6%) with ECOG score ≥2. The number of chemotherapy courses received before transfusion was 2-15, the median number of chemotherapy courses was 5. There were 32 autogenous CAR-T cells and 2 donor-derived CAR-T cells, 11 of them received allogeneic hematopoietic stem cell transplantation (allo-HSCT) before transfusion. All were mouse CAR-T cells. Fludarabine + Cyclophosphamide (FC) regimen was used for pretreatment before transfusion, and the number of CAR-T cells was 1 ~ 13.4×10 6/kg. Results All 34 patients received CD19-targeted CAR-T cell therapy. 22 patients obtained MRD- after 1 month, CR rate was 64.7%. 20 patients maintained MRD- after 2 months, and the CR rate was 58.8%. 13 patients still maintained MRD- after 3 months, with a CR rate of 38.2%. 4 patients with recurrence presented CD19 negative recurrence. 10 patients underwent Allo-HSCT after CR acquisition, 6 of them maintained a continuous CR state, and 4 patients died after recurrence. Cytokines release syndrome (CRS) was observed in 31 patients (91.2%). Among them, there were 20 patients (64.5%) with grade 1 ~ 2, 8 patients (25.8%) with grade 3 ~ 4, and 3 patients (9.7%) with grade 5. The cytokines levels of IL-6 and IFN-γ were mainly increased in 20 (64.5%) and 18 (58.1%) patients, respectively. Common clinical adverse reactions are: fever with 32 cases (94.1%), pancytopenia with 28 cases (82.4%), chills with 17 cases (50.0%), fatigue with 26 cases (76.5%), hypotension with 27 cases (79.4%), tachycardia with 24 cases (70.6%), hypofibrinogenemia with 20 cases (58.8%), hypoproglobinemia with 27 cases (79.4%), neurotoxicity with 15 cases (44.1%), nausea with 16 cases (47.1%), vomiting with 14 cases (41.2%), hypoalbuminemia with 25 cases (73.5%), transaminase eleations with 16 cases (47.1%), electrolyte metabolic disorders with 27 cases (79.4%) , hypoxemiawith 15 cases (44.1%). Conclusion CAR-T cells therapy is a novel method for the treatment of refractory/recurrent B-ALL with CD19 antigen positive, which can make patients achieved complete remission in a short time, even achieved MRD negative, and most of the CRS appeared in the process of treatment can be controlled by treatment, but the recurrence rate is higher after 3 months later, and can appear CD19 negative relapse. Allo-HSCT as soon as possible after obtaining CR can enable some patients to obtain sustained CR.Therefore, more clinical studies are needed to explore the clinical application of CAR-T cell therapy. Currently, it is believed that bridging with allo-HSCT may be a solution to achieve sustained CR. 【Key words】Chimeric antigen receptor T-cell; Relapsed/refractory acute lymphoblast leukemia; Efficacy; Safety; Cytokine release syndrome Disclosures No relevant conflicts of interest to declare.

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