The Landscape of CAR T Cells Beyond Acute Lymphoblastic Leukemia for Pediatric Solid Tumors

2018 ◽  
pp. 830-837 ◽  
Author(s):  
Christopher DeRenzo ◽  
Giedre Krenciute ◽  
Stephen Gottschalk
Keyword(s):  
T Cells ◽  
Brain Tumors ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Lymphoblastic Leukemia ◽  
Adoptive Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Pediatric Solid Tumors ◽  
Car T

Adoptive cell therapy with genetically modified T cells holds the promise to improve outcomes for children with recurrent/refractory solid tumors and has the potential to reduce treatment complications for all patients. Although T cells that express chimeric antigen receptors (CARs) specific for CD19 have had remarkable success for B-cell–derived malignancies, which has led to their approval by the U.S. Food and Drug Administration, CAR T cells have been less effective for solid tumors and brain tumors. Lack of efficacy is most likely multifactorial, but heterogeneous antigen expression; limited migration of T cells to tumor sites; and the immunosuppressive, hostile tumor microenvironment have emerged as major roadblocks that must be addressed. In this review, we summarize the clinical experience with CAR T-cell therapy for pediatric solid tumors, including brain tumors. In addition, we review strategies that have been and are being developed to enhance their antitumor activity.

scholarly journals CAR T-cell therapy of solid tumors: promising approaches to modulating antitumor activity of CAR T cells

2019 ◽  
pp. 5-12 ◽  
Author(s):  
Ya.Yu. Kiseleva ◽  
A.M. Shishkin ◽  
A.V. Ivanov ◽  
T.M. Kulinich ◽  
V.K. Bozhenko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Functional Activity ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Adoptive immunotherapy that makes use of genetically modified autologous T cells carrying a chimeric antigen receptor (CAR) with desired specificity is a promising approach to the treatment of advanced or relapsed solid tumors. However, there are a number of challenges facing the CAR T-cell therapy, including the ability of the tumor to silence the expression of target antigens in response to the selective pressure exerted by therapy and the dampening of the functional activity of CAR T cells by the immunosuppressive tumor microenvironment. This review discusses the existing gene-engineering approaches to the modification of CAR T-cell design for 1) creating universal “switchable” synthetic receptors capable of attacking a variety of target antigens; 2) enhancing the functional activity of CAR T cells in the immunosuppressive microenvironment of the tumor by silencing the expression of inhibiting receptors or by stimulating production of cytokines.

scholarly journals Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 125 ◽  
Author(s):  
Aleksei Titov ◽  
Aygul Valiullina ◽  
Ekaterina Zmievskaya ◽  
Ekaterina Zaikova ◽  
Alexey Petukhov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors.

scholarly journals Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for Adult Patients with Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 846-846
Author(s):  
Liang Huang ◽  
Na Wang ◽  
Chunrui Li ◽  
Yang Cao ◽  
Yi Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Antigen Loss

Abstract Clinical trials of second generation chimeric antigen receptor engineered T cells (CAR-T cells) have yielded unprecedented efficacy in refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL), especially in children and young adult. However, antigen loss relapse has been observed in approximately 14% of patients in anti-CD19 CAR-T cell therapy across institutions, which emerges as a challenge for the long-term disease control of this promising immunotherapy. Recently, CD19/CD20 and CD19/CD22 dual antigen targeting have been proposed to overcome antigen loss relapse after the administration of anti-CD19 CAR-T cells. This strategy may result in enhanced anti-tumor activity, while safety concern regarding the risk of cytokine release syndrome (CRS) due to significant CAR-T cell activation and cytokine release needs to be addressed. Here, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells. We aimed to evaluate its safety and efficacy in adult patients with refractory or relapsed B-ALL. This trial is registered with ChiCTR, number ChiCTR-OPN-16008526. Between March 2016 and March 2017, 27 patients with refractory or relapsed B-ALL were enrolled in this clinical trial, with a median age of 30±12 years (range, 18-62 years). Thirteen patients (48.1%) had a history of at least two prior relapsed or primary refractory disease. Twenty-six patients received fludarabine and cyclophosphamide before the infusion of CAR-T cells. The median cell dosages of anti-CD22 and anti-CD19 CAR-T cells were 2.44 ± 1.02 × 106 /kg and 1.98 ± 1.05 × 106 /kg, respectively. 24/29 (88.9%) patients achieved CR or Cri, including 7 patients who received prior hematopoietic stem cell transplantation, and 13/27 (48.1%) patients achieved minimal residual disease negative (MRD-) CR accessed by flow cytometry. Sustained remission was achieved with a 6-month overall survival rate of 79% (95% CI, 66-97) and an event-free survival rate of 72% (95% CI, 55-95). 24/29 (88.9%) patients experienced CRS and 6/27 (22.2%) patients had reversible sever CRS (grade 3-4). And 3/27 (11.1%) patients developed neurotoxicity. Multi-color flow cytometry was used to screen and quantitate MRD in blood, bone marrow and cerebrospinal fluid. Antigen escape of CD19 and CD22 was not detected in any relapsed patient post-CAR-T cell therapy. Our results indicated that sequential infusion of third generation Anti-CD22 and Anti-CD19 CAR-T cell therapy is feasible and safe for patients with refractory/relapsed B-ALL. Dual antigen targeting should be a promising approach for overcoming antigen escape relapse, while needs to be further determined in our clinical trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals New Generation Chimeric Antigen Receptor T-Cell Therapy (CoupledCAR) Induces High Rate Remissions in Solid Tumor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4631-4631
Author(s):  
Lei Xiao
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Thyroid Cancer ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Tumor Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

New Generation Chimeric Antigen Receptor T-Cell Therapy ( CoupledCAR ) Induces High Rate Remissions in Solid Tumor Yu Liu1,Song Li2,Youli Luo3,Haixia Song4,Chengfei Pu5, Zhiyuan Cao 5, Cheng Lu5,Yang Hang5,Xi Huang5,Xiaogang Shen5 ,Xiaojun Hu3 , Renbin Liu1,Xiuwen Wang2,Junjie Mao3,Shihong Wei4 ,Zhao Wu5and Lei Xiao5* 1.The Third Affiliated Hospital, SUN YAT-SEN University 2.Qilu Hospital of Shandong University 3.The Fifth Affiliated Hospital, SUN YAT-SEN University 4.Gansu Procincial Cancer Hospital 5.Innovative Cellular Therapeutics *Corresponding to: Lei Xiao, [email protected] Chimeric antigen receptor (CAR) T cell therapy made significant progress for treating blood cancer such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges, such as physical barrier, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and cell expansion in vivo for treatment of solid tumors Conventional CAR T cell therapy showed weak CAR T expansion in patients and thus achieved no or little response for treating solid tumors. Here, we generated "CoupledCAR" T cells including an anti-TSHR CAR molecule. Compared with conventional CART cells,these "CoupledCAR" T cells successfully improved the expansion of CART cells more than 100 times and enhanced CAR T cells' migration ability, allowing the CAR T cells to resist and infiltrate the tumor microenvironment and killed tumor cells. To verify the effect of "CoupledCAR" T cells on solid tumors, we have completed several clinical trials for different solid tumors, including two patients with thyroid cancer. Immunohistochemistry (IHC) results showed that thyroid stimulating hormone receptors (TSHR) were highly expressed in thyroid cancer cells. In vitro co-culture experiments showed that TSHR CAR T cells specifically recognized and killed TSHR-positive tumor cells. Animal experiments showed that TSHR CAR T cells inhibited the proliferation of TSHR-positive tumor cells. Therefore, we designed "CoupledCAR" T cells expressing a binding domain against TSHR. Further,we did clinical trials of two group patients that were successfully treated using conventional TSHR CAR T cells and the "CoupledCAR" T cells, respectively. In the first group using conventional TSHR CAR T cells, patients showed weak cell expansion and less migration ability. In the group using TSHR "CoupledCAR" T cells, patients showed rapid expansion of CAR T cells and killing of tumor cells. One month after infusion (M1), the patient was evaluated as PR(Partial Response): the lymph node metastasis disappeared, and thoracic paratracheal tumors decreased significantly. Three months after infusion (M3), the patient was evaluated as a durable response, and the tumor tissue was substantially smaller than M1. Further, two patients with colonrectal cancer were enrolled in this trial and infused "CoupledCAR" T cells. One patient achieved PR and the other one achieved SD (Stable Disease). Therefore, "CoupledCAR" T cells can effectively promote expansion, migration and killing ability of CAR T cells in patients with thyroid cancer. "CoupledCAR" T cell technology is a technological platform, which may be used to treat other cancer types. Next, we are recruiting more patients with solid tumors in clinical trials using "CoupledCAR" T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy

2019 ◽  
Vol 3 (22) ◽  
pp. 3539-3549 ◽  
Author(s):  
Vinodh Pillai ◽  
Kavitha Muralidharan ◽  
Wenzhao Meng ◽  
Asen Bagashev ◽  
Derek A. Oldridge ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Key Points ◽  
Car T ◽  
Rate Of Failure ◽  
Cd19 Expression

Key Points Preinfusion dim CD19 expression and rare CD19– events in B-ALL do not affect relapses or responses to CD19-directed CAR T-cells. Prior blinatumomab treatment increases the rate of failure to achieve MRD– remission and CD19– MRD and relapse.

scholarly journals CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors

2019 ◽  
Vol 25 (8) ◽  
pp. 2560-2574 ◽  
Author(s):  
Robbie G. Majzner ◽  
Johanna L. Theruvath ◽  
Anandani Nellan ◽  
Sabine Heitzeneder ◽  
Yongzhi Cui ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Tumors ◽  
Solid Tumors ◽  
Cancer Antigen ◽  
Car T Cells ◽  
Pediatric Solid Tumors ◽  
Car T ◽  
Pan Cancer

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 CAR-T cell therapy: current limitations and potential strategies

2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Robert C. Sterner ◽  
Rosalie M. Sterner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Anti Tumor Activity

AbstractChimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

scholarly journals Chimeric Antigen Receptor (CAR) T Cell Therapy for Digestive Tumor

2021 ◽  
Vol 271 ◽  
pp. 03065
Author(s):  
Chang Wu ◽  
Jun Wu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Dietary Habits ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Digestive tumors commonly include esophageal cancer, gastric cancer, liver cancer, pancreatic cancer. Most of which are malignant tumors. All of the tumors do strong harm to human body and seriously affect the physical and mental health of patients. With the change of modern dietary habits, the morbidity of digestive tumors is increasing year by year, and the threat to the society is increasingly intensified. Traditional treatments for digestive tumors include surgical resection, chemotherapy and radiotherapy, all of which can alleviate the symptoms to some extent, but there are still many drawbacks. Compared with traditional therapy, immunotherapy has better therapeutic effect and fewer adverse reactions. Immunotherapy is to activate the human immune system and kill tumor cells by its own immune function. In immunotherapy, CAR-T cell therapy, a kind of personalized therapy that takes effect through gene modification to obtain T cells carrying tumor antigen-specific receptor, occupies a leading position. At present, CAR-T cells have shown excellent results in the treatment of lymphoid and hematopoietic tumors, on the contrast, there are few studies on the treatment of solid tumors. In this article, we summarized the application of some CAR-T cells in solid tumors of the digestive system.

scholarly journals Tandem CAR T Cells Targeting CD19 and CD22 Is a Safe and Highly Efficacious Treatment for Relapse/ Refractory ALL Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1338-1338 ◽  
Author(s):  
Xiaowen Tang ◽  
Liqing Kang ◽  
Wei Qi ◽  
Wei Cui ◽  
Haiping Dai ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
Tumor Burden ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
One Year ◽  
Dual Target

Background: CAR-T immunotherapy has shown remarkable promising results for relapsed/ refractory (R/R) acute lymphoblastic leukemia (ALL). However, CD19-targeted CAR T cell therapy for R/R ALL has a relapse rate of approximately 50% at 1 year after CART therapy, and the most common mechanism of relapse is due to CD19 antigen loss or decreased target expression on the surfaces of the lymphoblastic leukemia cells. Potential approaches to overcome this challenge include engineering CAR T cells to achieve multispecificity and to respond to lower expression levels of target antigens by dual target CAR T strategies. Objective: In order to evaluate the efficacy and safety of CD19/CD22 dual target CAR T cells for R/R ALL patients to determine if targeting multiple antigens can prevent treatment failure and improve response rates and durability of response. Method: A novel CAR T cells with tandem targeting CD19 and CD22 antigens and a third generation CAR construct of CD28 and OX40 co-stimulatory domains were administered to 23 patients with R/R ALL with a median age of 24(6-56)years. High-risk patients were enrolled in this cohort, including 10 with BCR-ABL+ALL (6 of 10 with T 315I mutation), 4 with TP53 mutation, 2 with Ph-like ALL and 3 with relapsed ALL post allo-HSCT. The patients received a single infusion of CAR T cells with dose escalation schedule:10%--30%--60%. The median infusion dose of CAR T cells was 1 (0.5- 2.5) ×107cells/kg. Results: The median follow-up was 9 (3.5-20) months. The day 28 CR/CRi rate was 100% with21/22 (95.5%) molecular remission. Six-month OS was 94.4% and RFS was 76.9%. One-year OS was 57.2% and RFS was 67.3%. One-year OS of high tumor burden (BM blast> 30%)(15/22) and low tumor burden(BM blast≤30%)(7/22) was 47.5% and 75% respectively (p>0.05). The 1-year OS of the CAR T- to- allo-HSCT group(14/22) was better than that of the non-transplant group(8/22) (OS 72.9% vs. 26.7%, p = 0.116). The cumulative relapse rate of 6 months and 1 year were 23.1% and 32.7% respectively. The overall incidence of CRS were 91% included 22.7%grade III CRS ,4.5% grade IV CRS and 0% severe CRES. Only one patient presented MAH syndrome and was cured with low dose dexamethasone. There was no CAR T-related death. Conclusions: The tandem CD19/CD22 dual target CAR T cells therapy is a safe and high efficacy treatment for R/R ALL patients. It is possible that multi-targeted CAR-T cell therapy may overcome this resistance mechanism and improve clinical outcomes. Disclosures No relevant conflicts of interest to declare.

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