scholarly journals Novel CD37, Humanized CD37 and Bi-Specific Humanized CD37-CD19 CAR-T Cells Specifically Target Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 981
Author(s):  
Vita Golubovskaya ◽  
Hua Zhou ◽  
Feng Li ◽  
Michael Valentine ◽  
Jinying Sun ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell Lymphoma ◽  
Parental Cell ◽  
Parental Cell Line ◽  
Ifn Gamma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Positive Target

CD19 and CD37 proteins are highly expressed in B-cell lymphoma and have been successfully targeted with different monotherapies, including chimeric antigen receptor (CAR)-T cell therapy. The goal of this study was to target lymphoma with novel CD37, humanized CD37, and bi-specific humanized CD37-CD19 CAR-T cells. A novel mouse monoclonal anti-human CD37 antibody (clone 2B8D12F2D4) was generated with high binding affinity for CD37 antigen (KD = 1.6 nM). The CD37 antibody specifically recognized cell surface CD37 protein in lymphoma cells and not in multiple myeloma or other types of cancer. The mouse and humanized CD37-CAR-T cells specifically killed Raji and CHO-CD37 cells and secreted IFN-gamma. In addition, we generated bi-specific humanized hCD37-CD19 CAR-T cells that specifically killed Raji cells, CHO-CD37, and Hela-CD19 cells and did not kill control CHO or Hela cells. Moreover, the hCD37-CD19 CAR-T cells secreted IFN-gamma against CD37-positive and CD19-positive target CHO-CD37, Hela-CD19 cells, respectively, but not against CD19 and CD37-negative parental cell line. The bi-specific hCD37-CD19 significantly inhibited Raji xenograft tumor growth and prolonged mouse survival in NOD scid gamma mouse (NSG) mouse model. This study demonstrates that novel humanized CD37 and humanized CD37-CD19 CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells and provides a basis for future clinical studies.

scholarly journals DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Martina Pennisi ◽  
Marta Garcia-Recio ◽  
Jessica R. Flynn ◽  
Aishat Afuye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

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.

Presence of Endogenous TCR Antigen in Vivo Attenuates Efficacy of Anti-CD19 Targeted CAR T Cell Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3721-3721
Author(s):  
Yinmeng Yang ◽  
Christopher Daniel Chien ◽  
Elad Jacoby ◽  
Haiying Qin ◽  
Waleed Haso ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Ifn Gamma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Adoptive therapy using T cells genetically engineered to express chimeric antigen receptors (CAR) has proven extremely effective against acute lymphoblastic leukemia (ALL) in clinical trials with the use of anti-CD19 CAR T cells. Most CAR T cell protocols use autologous T cells, which are then activated, transduced with the anti-CD19 CAR, and expanded ex-vivo before infusion back into the patient. This approach minimizes the risk of graft-versus-host disease (GVHD) even in allogeneic transplant recipients, due to tolerization of the donor T cell repertoire in the recipient. However, many patients have heavy disease burden and lymphopenia due to previous treatments, which makes the isolation of healthy T cells difficult. Thus, centers are exploring the potential of allogeneic T cell donors and the possibility of universal T cell donors for CAR-based therapy including the use of virus-specific T cells. In these cases, in addition to the chimeric receptor specificity, the transduced T cell population will also have reactivity against target antigens through the endogenous TCR. However, little is known about the impact of signaling of the endogenous TCR on CAR T cell activity, particularly in vivo. To test this, we used a syngeneic transplantable ALL murine model, E2aPBx, in which CD19 CAR T cells can effectively eradicate ALL. CD4 (Marilyn) and CD8 (Matahari) T cells from syngeneic HY-TCR transgenic donors specific for the minor histocompatibility male antigen, HY, were used as CAR T cell donors to control for endogenous TCR reactivity. Splenic T cells isolated from Matahari, Marilyn, or B6 mice were activated ex-vivo using anti-CD3/anti-CD28 beads, with the addition of IL2 and IL7. T cells were transduced with a retroviral vector expressing a murine CAR composed of anti-CD19 scfv/CD28/CD3ζ on days two and three. CAR T cells are evaluated in vitro by CD107a degranulation assay and INF gamma ELISA. In response to HY peptide alone or HY+CD19- line M39M, transduced CD8 HY (Matahari) cells produced IFN gamma and expressed CD107a whereas transduced CD4 HY (Marilyn) cells only produced IFN gamma. Interestingly, in response to CD19+HY- ALL, both Matahari and Marilyn expressed CD107a and produced IFN gamma indicating that CD4 T cells can acquire CD8-like lytic activity when stimulated through a CAR receptor. When CD19 CAR transduced Marilyns and Mataharis were stimulated in the presence of HY and CD19, CD8 Mataharis had an attenuated effect against CD19, suggesting that the presence of antigen activated TCR adversely affects the potency of the CAR receptor. Efficacy of the HY and polyclonal CAR T cells were next tested in-vivo in male and female B6 mice. Mice were given 1E6 E2aPBx ALL leukemia cells on day 1, and received 500 rads sub-lethal total body irradiation on day 4 as a lymphodepleting regimen. On day 5, mice were given a low (1E5) or high (5E6) dose of CAR T cells. There was a statistically significant (p=0.0177) improvement in the survival of female versus male mice after treatment with the CD4+ HY specific anti-CD19 CAR T cells, and female mice that received HY anti-CD19 CAR T cells survived longer than untreated control females (p=0.01). Remarkably, the survival of male mice that received HY anti-CD19 CAR T cells was statistically worse than untreated control males (p=0.008). This suggests that the presence of TCR antigen negatively impacts the function of CAR T cells. Furthermore, in a separate experiment using an equally mixed population of Marilyn (CD4+) and Matahari (CD8+) HY specific T cells, males has a statistically significantly (p=0.0116) worse survival compared to females after receiving 5E5 HY specific T cells. In conclusion, simultaneous stimulation through both CAR and TCR results in attenuated cytokine production and degranulation by CD8 T cells. In vivo, in the presence of the endogenous TCR antigen, both CD4 and CD8 CAR T cells are less potent at eradicating leukemia. These have implications for the development of universal donors for CAR T cell therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD229 CAR T Cell Therapy for the Treatment of Relapsed B Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2800-2800
Author(s):  
Michael Olson ◽  
Tim Luetkens ◽  
Fiorella Iglesias ◽  
Sabarinath Radhakrishnan ◽  
Jennie Y. Law ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract B cell lymphoma is the most common hematologic malignancy in the United States. Although treatment options have greatly improved in the past several decades, outcomes for patients with relapsed B cell lymphoma remain poor. Chimeric antigen receptor (CAR) T cells have recently entered the clinic with promise to address the gap in effective therapies for patients relapsed B cell lymphoma. However, antigen loss and poor CAR T cell persistence has been shown to drive resistance to the widely approved CD19-targeted CAR in some patients, demonstrating the need for additional therapies. Here, we demonstrate CD229-targeted CAR T cell therapy as a promising option for the treatment of relapsed B cell lymphoma, addressing an important group of patients with typically poor outcomes. CD229 is an immune-modulating receptor expressed on the surface of B cells that we recently found to be highly expressed in the plasma cell neoplasm multiple myeloma (Radhakrishnan et al. 2020). We utilized semi-quantitative PCR and flow cytometry to assess whether CD229 is also expressed on malignant B cells earlier in development as found in B cell lymphoma. Expression analysis revealed the presence of CD229 in a panel of 11 B cell lymphoma cell lines and 45 primary B cell lymphoma samples comprising several subsets of disease including aggressive B cell lymphomas such as diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and Burkitt lymphoma as well as indolent subtypes of B cell lymphoma including chronic lymphoblastic leukemia (CLL) and follicular lymphoma. Of note, CD229 was found to be overexpressed on primary B cell lymphoma cells when compared to autologous normal B cells. Given the high levels of CD229 expression throughout all B cell lymphoma subtypes analyzed, we generated CD229 CAR T cells in order to determine whether CAR T cell therapy is an effective way to target CD229 expressing B cell lymphoma cells. CD229 CAR T cells exhibited robust cytotoxicity when cocultured with B cell lymphoma cell lines and primary samples characterized by significant production of TH1 cytokines IL-2, TNF and IFNγ and rapid loss of B cell lymphoma cell viability when compared to control CAR T cells lacking an antigen binding scFv domain (∆scFv CAR T cells). In vivo analysis revealed effective tumor control in NSG mice carrying B cell lymphoma cell lines JeKo-1 (MCL) and DB (DLBCL) when treated with CD229 CAR T cells versus ∆scFv CAR T cells. Finally, we sought to determine the efficacy of CD229 CAR T cells in the context of CD19 CAR T cell therapy relapse. Here, a 71-year-old patient with CLL had an initial response when treated with CD19 CAR T cells but quickly relapsed only 2 months after treatment. Malignant cells from the CLL patient retained CD229 expression as identified by flow cytometry and an ex vivo coculture with CD229 CAR T cells revealed robust killing of CLL cells by CD229 CAR T cells. Transfer of antigen from target cell to CAR T cell by trogocytosis was recently suggested to drive relapse following CAR T cell therapy by decreasing antigen on tumor cells and promoting CAR T cell fratricide (Hamieh et al. 2019). We cocultured CD19 and CD229 CAR T cells with primary CLL cells and assessed CD19 and CD229 expression as well as CAR T cell viability by flow cytometry. In contrast with CD19 CAR T cells, CD229 CARs did not strip their target antigen from the surface of CLL cells. The transfer of CD19 from CLL cells to CD19 CAR T cells resulted in poor CAR T cell viability while CD229 CAR T cell viability remained high following coculture. In summary, we demonstrate that CD229 is a promising therapeutic target in B cell lymphoma due to its high levels of expression throughout many subtypes of disease. CD229 CAR T cells effectively kill B cell lymphoma cells in vitro and control growth of aggressive B cell lymphomas in vivo. Finally, CD229 CAR T cells are effective against primary CLL cells from patients that have relapsed from CD19 CAR T cell therapy and do no exhibit antigen loss by trogocytosis. Taken together, these data suggest that CD229 CAR T cell therapy may be a promising option to address the poor outcomes for patients with relapsed B cell lymphoma. Disclosures No relevant conflicts of interest to declare.

scholarly journals Case Report: Sirolimus Alleviates Persistent Cytopenia After CD19 CAR-T-Cell Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Limin Xing ◽  
Yihao Wang ◽  
Hui Liu ◽  
Shan Gao ◽  
Qing Shao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor T (CAR-T) cells show good efficacy in the treatment of relapsed and refractory B-cell tumors, such as acute B-cell leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). The main toxicities of CAR-T include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cytopenia, and severe infection. It is still very difficult for CAR-T to kill tumor cells to the maximum extent and avoid damaging normal organs. Here, we report a case of DLBCL with persistent grade 4 thrombocytopenia and severe platelet transfusion dependence treated with CD19 CAR-T cells. We used sirolimus to inhibit the sustained activation of CAR-T cells and restore normal bone marrow hematopoiesis and peripheral blood cells. Moreover, sirolimus treatment did not affect the short-term efficacy of CAR-T cells, and DLBCL was in complete remission at the end of follow-up. In conclusion, sirolimus can represent a new strategy for the management of CAR-T cell therapy-related toxicity, including but not limited to hematotoxicity. However, further controlled clinical studies are required to confirm these findings.

CD19-Directed CAR T Cells Treatment in a Patient With Refractory DLBCL and CNS Involvement

2019 ◽  
pp. 16-21
Author(s):  
Alexander Ring ◽  
Antonia Maria Müller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Cns Involvement ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

ABSTRACT Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common neoplasm of the lymphatic system. Treatment and clinical management are difficult in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR) T cells are genetically engineered using autologous patient lymphocytes and have shown very promising results in the treatment of relapsed and refractory cases of DLBCL. Methods: A 64-year-old male patient with refractory DLBCL and central nervous system (CNS) involvement after 9 lines of therapy was treated with CD19-specific CAR T cell therapy at the Department of medical oncology and hematology at the University Hospital of Zurich and followed-up for 10 weeks. Results: Autologous lymphocytes were successfully harvested and transfected/expanded for CAR T cell production. Conditioning chemotherapy and CAR T infusion was well tolerated. Post-infusion side effects were mild (cytokine release syndrome [CRS] grade 1−2), with limited signs of neurotoxicity. Ten weeks after CAR T cell therapy, an excellent response could be documented via PET-CT. The CNS lesion disappeared as assessed via cranial MRI. Conclusion: CD19-targeted CAR T cell therapy is a revolutionary treatment option for heavily pre-treated R/R DLBCL even in the setting of CNS involvement.

scholarly journals CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yun Liang ◽  
Hui Liu ◽  
Zheming Lu ◽  
Wen Lei ◽  
Chaoting Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Salvage Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractCD19-targeted chimeric antigen receptor T (CAR T) cell therapy is a promising option to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, the majority of CAR T-treated patients will eventually progress and require salvage treatment, for which there is no current standard. In this study, we analyzed data from 6 patients with R/R DLBCL who experienced progression following CD19-CAR T therapy, and then received CD19-specific CAR T cells that express a PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR T) as salvage therapy at our institution. After the second infusion of CAR T cells, 3 of 6 patients achieved complete remissions and the duration of the response of responsive patients ranged from 8 to 25 months. One patient showed a stable disease. In contrast, 2/6 patients died on 60 days because of progression disease. Importantly, no severe neurologic toxicity or cytokine release syndrome was observed. These data suggest that CD19-PD-1/CD28-CAR-T cells, a novel anti-CD19 CAR-T cell therapy, elicit a potent and durable anticancer response, and can be used in the post-CD19-CAR T failure setting.

scholarly journals A Novel Method for Molecular Enumeration of Circulating Tisa-Cel and Axi-Cel in Lymphoma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Chiara Monfrini ◽  
Vanessa Aragona ◽  
Martina Magni ◽  
Riccardo Betta ◽  
Cristina Vella ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Post Infusion

Background: Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment in approximately 40% of relapsed/refractory lymphomas. High rates of complete remission (CR) observed in clinical trials, led to fast-track FDA and EMA approval and commercialization of two CD19-directed CAR T-cell products (tisagenlecleucel/Tisa-cel/Kymriah and axicabtagene ciloleucel/Axi-cel/Yescarta) for refractory/relapsed diffuse large B cell lymphoma (DLBCL) and primary mediastinal large B cell lymphoma (PMBCL). In these studies, CAR T-cell engraftment and in vivo expansion have a crucial impact on disease response and toxicity. It is of paramount importance to develop homogeneous standardized approaches for monitoring expansion and persistence of CAR T-cells also in the case of cells not detectable by flow cytometry (FCM) as these data can guide clinical decision making. Aims of this study were: to assess relevant time-points for FCM analysis across the different products to develop a unique quantitative PCR assay to detect both tisa-cel and axi-cel. Methods: We prospectively collected samples from 28 patients (pts) (16 DLBCL, 5 transformed follicular lymphoma and 7 PMBCL) treated with axi-cel (n=15) and tisa-cel (n=13) at the Fondazione IRCCS Istituto Nazionale Tumori between Nov 2019 and July 2020. CAR T-cells were monitored in the peripheral blood (PB) on days 0, 4, 7, 9, 14, 21, 28 and monthly post infusion by FCM. Cells were stained with CD19 CAR Detection Reagent (Miltenyi), Anti-Biotin-PE, CD3-FITC, CD4-VioGreen, CD8-APC-Vio770, CD45-VioBlue, CD14-APC and 7-AAD Staining Solution and analyzed by FCM using the MACSQuant® Analyzer (Miltenyi). To evaluate CAR T-cell persistence, we also generated a unique droplet digital PCR (ddPCR) primer-probe assay to target both tisagen-cel and axi-cel. We obtained a partial cDNA sequence of the two CAR constructs by amplification and direct sequencing of fragments generated with primers designed by educated guess to bind to the anti-CD19 murine single-chain variable fragment (scFV) and to the CD8α or CD28 trans-membrane regions of tisagen-cel and axi-cel vectors respectively. The assay was used to quantify CAR+ cells on genomic DNA extracted from PB cells collected serially after infusion. FCM and molecular data were correlated to outcome. Results: Peak expansion of CAR T-cells by FCM occurred within the first 14 days post-infusion. At the point of maximal expansion, collectively a mean of 17% of circulating CD3+ T cells were CAR+ and CAR+ cells were more abundant among CD3+ cells in pts receiving axi-cel (26% vs 8.5% for tisagen-cel, p<0.05). Patients achieving CR at 1 month from CAR T-cell therapy (n=10) had significantly more CAR+ cells at day 9 than non-CR pts (mean 146 vs 18 CAR+ cells/ul, p<0.05) and their magnitude of expansion in the first 14 days was higher than the one of non-CR pts (mean area under the curve (AUC)= 1110 vs 177; p<0.05). A cut-off value of CAR+ cells at day 9>62/ul was prognostic with sensitivity of 67% and specificity of 76% (Receiver operating characteristic analysis). At subsequent time points the number of CAR T-cells decreased, but continued to be detectable by FCM up to 6 months post infusion although at very low levels (mean 2 CAR+ cell/ul) irrespective of outcome. To evaluate whether these low counts reliably represent CAR T+ cells or are rather signals due to aspecific binding of the antibodies, a ddPCR assay was set up. The assay displayed an excellent separation between positive and negative droplets on both axi-cel and tisagen-cel products, good reproducibility and specificity with max standard deviation of 0.06 and no CAR positive signal in healthy donors. Additionally, the CAR specific signal was detectable up to the 0,01% dilution. FCM and ddPCR data had a good correlation (r=0.93, p<0.001): in accordance with FCM, ddPCR revealed a peak expansion of CAR+ signals at day 9 post infusion, followed by a progressive reduction of the CAR+ signal over time in all pts that becomes undetectable in case of relapse despite the presence of 1-2 cells/ul by FCM that probably represent aspecific findings. Conclusion: The combined use of FCM and the novel molecular assay facilitates the precise enumeration of commercial anti-CD19 CAR T-cells. Higher frequencies of CAR+ T cells at day 9 distinguish responders irrespectively of the product they received in our small prospective series. Updated results will be presented. Disclosures Chiappella: Servier: Honoraria; Roche: Honoraria; Takeda: Honoraria; Iqone: Honoraria; Janssen: Honoraria; Gilead-Kite: Honoraria; Celgene: Honoraria. Corradini:Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; BMS: Other; Takeda: Consultancy, Honoraria, Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for.

scholarly journals CSPG4 as Target for CAR-T-Cell Therapy of Various Tumor Entities–Merits and Challenges

2019 ◽  
Vol 20 (23) ◽  
pp. 5942 ◽  
Author(s):  
Dennis C. Harrer ◽  
Jan Dörrie ◽  
Niels Schaft
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Target Antigen ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Targeting cancer cells using chimeric-antigen-receptor (CAR-)T cells has propelled adoptive T-cell therapy (ATT) to the next level. A plentitude of durable complete responses using CD19-specific CAR-T cells in patients suffering from various lymphoid malignancies resulted in the approval by the food and drug administration (FDA) of CD19-directed CAR-T cells for the treatment of acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). A substantial portion of this success in hematological malignancies can be traced back to the beneficial properties of the target antigen CD19, which combines a universal presence on target cells with no detectable expression on indispensable host cells. Hence, to replicate response rates achieved in ALL and DLBCL in the realm of solid tumors, where ideal target antigens are scant and CAR-T cells are still lagging behind expectations, the quest for appropriate target antigens represents a crucial task to expedite the next steps in the evolution of CAR-T-cell therapy. In this review, we want to highlight the potential of chondroitin sulfate proteoglycan 4 (CSPG4) as a CAR-target antigen for a variety of different cancer entities. In particular, we discuss merits and challenges associated with CSPG4-CAR-T cells for the ATT of melanoma, leukemia, glioblastoma, and triple-negative breast cancer.

scholarly journals Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4279
Author(s):  
Sylvain Lamure ◽  
François Van Laethem ◽  
Delphine De Verbizier ◽  
Claire Lozano ◽  
Eve Gehlkopf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.

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