scholarly journals A T-cell independent universal cellular therapy strategy through antigen depletion

2021 ◽  
Author(s):  
Dan Li ◽  
Wenbin Wang ◽  
Shufeng Xie ◽  
Maolin Ge ◽  
Ruiheng Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Therapy ◽  
Patient Specific ◽  
Therapy Strategy ◽  
Artificial Antigen ◽  
Car T ◽  
Antigen Loss ◽  
Cd19 Expression ◽  
Cellular Therapeutics

CD19-targeting chimeric antigen receptor (CAR) T-cell therapeutics is a revolutionary, novel and successful treatment for B-cell malignancies. However, while CD19-CAR-T therapy can obtain high rates of complete responses in these patients, a significant fraction of patients may experience CD19-negative relapse. Moreover, the dependency on T-cell mediated cytotoxicity restricts CAR-T therapy as a patient-specific individualized therapy with severe side effects such as cytokine-release syndrome (CRS). Whether CAR-T therapy can be substituted by a non-T-cell based universal cellular therapy is largely unknown. Surprisingly, we have demonstrated here that T-lymphocytic cells, as well as non-lymphocytic cells, can cause CD19 internalization and subsequent depletion when they are armed with a CD19-recognizing moiety. This CD19 antigen depletion can efficiently induce T-cell independent apoptosis in target cancer cells whose survival is dependent upon CD19 expression, suggesting that CD19 antigen depletion constitutes a crucial tumor destroying mechanism for CD19-CAR-T, especially for its long-term efficacy. We therefore proposed a universal strategy for CRS-free cellular therapeutics, utilizing artificial antigen-recognizing cells (AARC), which can be manufactured universally and standardly as off-the-shelf mesenchymal stromal cells (MSCs) or other types of non-autologous cell expressing anergic CARs. Our results not only uncovered an unrecognized mechanism for CAR-T cytotoxicity and antigen loss, but also shed new insight into a shift in cellular therapeutics from unique patient-specific autologous therapeutics, to universal and standardized allogeneic treatment.

scholarly journals Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Blood ◽  
2016 ◽  
Vol 128 (3) ◽  
pp. 360-370 ◽  
Author(s):  
Vijay G. Bhoj ◽  
Dimitrios Arhontoulis ◽  
Gerald Wertheim ◽  
James Capobianchi ◽  
Colleen A. Callahan ◽  
...  
Keyword(s):  
T Cell ◽  
Humoral Immunity ◽  
Plasma Cells ◽  
T Cell Therapy ◽  
Cell Immunotherapy ◽  
Car T Cell Therapy ◽  
Key Points ◽  
Car T ◽  
Cd19 Expression

Key PointsCD19-targeted T-cell immunotherapy reveals that a population of PCs lacking CD19 expression survives long-term, independent of B cells. Preexisting humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia after CTL019 immunotherapy.

scholarly journals Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

2020 ◽  
Vol 38 (32) ◽  
pp. 3805-3815
Author(s):  
Kathryn M. Cappell ◽  
Richard M. Sherry ◽  
James C. Yang ◽  
Stephanie L. Goff ◽  
Danielle A. Vanasse ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

PURPOSE Anti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy. METHODS Between 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326 ). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells. RESULTS The percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051). CONCLUSION Complete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.

scholarly journals A Preclinical Embryonic Zebrafish Xenograft Model to Investigate CAR T Cells in Vivo

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 567 ◽  
Author(s):  
Susana Pascoal ◽  
Benjamin Salzer ◽  
Eva Scheuringer ◽  
Andrea Wenninger-Weinzierl ◽  
Caterina Sturtzel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cellular Therapy ◽  
Xenograft Model ◽  
Model Systems ◽  
Preclinical Model ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T cells have proven to be a powerful cellular therapy for B cell malignancies. Massive efforts are now being undertaken to reproduce the high efficacy of CAR T cells in the treatment of other malignancies. Here, predictive preclinical model systems are important, and the current gold standard for preclinical evaluation of CAR T cells are mouse xenografts. However, mouse xenograft assays are expensive and slow. Therefore, an additional vertebrate in vivo assay would be beneficial to bridge the gap from in vitro to mouse xenografts. Here, we present a novel assay based on embryonic zebrafish xenografts to investigate CAR T cell-mediated killing of human cancer cells. Using a CD19-specific CAR and Nalm-6 leukemia cells, we show that live observation of killing of Nalm-6 cells by CAR T cells is possible in zebrafish embryos. Furthermore, we applied Fiji macros enabling automated quantification of Nalm-6 cells and CAR T cells over time. In conclusion, we provide a proof-of-principle study that embryonic zebrafish xenografts can be used to investigate CAR T cell-mediated killing of tumor cells. This assay is cost-effective, fast, and offers live imaging possibilities to directly investigate CAR T cell migration, engagement, and killing of effector cells.

scholarly journals Industry’s Giant Leap Into Cellular Therapy: Catalyzing Chimeric Antigen Receptor T Cell (CAR-T) Immunotherapy

2019 ◽  
Vol 14 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Stacie Ittershagen ◽  
Solveig Ericson ◽  
Lamis Eldjerou ◽  
Ali Shojaee ◽  
Eric Bleickardt ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Cellular Therapy ◽  
Antigen Receptor ◽  
Car T ◽  
Giant Leap

scholarly journals Long-term remission in multiply relapsed enteropathy-associated T-cell lymphoma following CD30 CAR T-cell therapy

2020 ◽  
Vol 4 (23) ◽  
pp. 5925-5928
Author(s):  
Timothy J. Voorhees ◽  
Nilanjan Ghosh ◽  
Natalie Grover ◽  
Jared Block ◽  
Catherine Cheng ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Key Points ◽  
Car T

Key Points CD30 CAR T-cell therapy promoted a prolonged remission in a patient with multiply relapsed EATL.

scholarly journals Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts

2018 ◽  
Vol 23 (6) ◽  
pp. 1175-1182 ◽  
Author(s):  
Ping-Pin Zheng ◽  
Johan M. Kros ◽  
Jin Li
Keyword(s):  
T Cell ◽  
Cell Therapies ◽  
Car T Cell ◽  
Safety Risks ◽  
Car T

scholarly journals Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management

2020 ◽  
Vol 4 (4) ◽  
pp. 676-686 ◽  
Author(s):  
Martina Pennisi ◽  
Tania Jain ◽  
Bianca D. Santomasso ◽  
Elena Mead ◽  
Kitsada Wudhikarn ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cellular Therapy ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Grading System ◽  
Immune Effector ◽  
Car T Cell ◽  
Grading Systems ◽  
Car T

Abstract Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell–related toxicity, cytokine release syndrome (CRS), and immune effector cell–associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.

Choice of Better T-cells for Adoptive Immunotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-22-SCI-22 ◽  
Author(s):  
Dirk Hans Busch
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
B Cell ◽  
Adoptive Immunotherapy ◽  
Car T Cells ◽  
Car T ◽  
Selective Depletion

Abstract Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. The definition of optimal targets and antigen receptors as well as the differentiation status of transferred T cells are emerging as crucial parameters for generating cell products with predictable efficacy and safety profiles. Our laboratory has demonstrated that defined subsets within the memory CD8+ T cell compartment fulfill all key characteristics of adult tissue stem cells and are essential for robust and long-term maintained responses upon adoptive transfer. We have developed clinical multi-parameter enrichment technologies to purify these memory stem cells for clinical applications. In my presentation I will report on the status of ongoing clinical trials using such purified cell products either as a primary T cell population for the treatment of infections upon allogeneic stem cell transplantation or after genetic modification with a CD19 CAR for the treatment of malignancies (collaboration with Stan Riddell, FHCC/Seattle). Infusing small numbers of T cells within a memory stem cell product can be highly effective therapeutically, but bears some risk of toxicity. Therefore, safeguards that allow selective depletion of transferred cells in the case of un-tolerable side effects may be needed to further improve adoptive immunotherapy. I will present results exploring the capacity of a truncated version of EGFR (EGFRt) co-expressed with T cells expressing a CD19-CAR. In pre-clinical mouse models we demonstrate that application of Cetuximab, which binds to EGFRt, confers selective depletion of adoptively transferred CAR-T cells in vivo. Long-term B cell aplasia, which is a main side effect of CD19-CAR T cell therapy, can be completely reverted with this strategy. Vaccination studies upon B cell recovery demonstrate full functionality of antigen-specific antibody formation. EGFRt co-expressing CD19-CAR T cells have been successfully transferred into first human patients, providing the option to test for the first time in a clinical setting whether treatment of B cell aplasia after long-term leukemia remission can be achieved by selective depletion. Disclosures Busch: STAGE cell therapeutics: Other: I was share holder of STAGE cell therapeutics, a company that was recently bought by Juno therapeutics.. Off Label Use: CD19 CAR T cells.

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