scholarly journals New Therapeutic Approach for Central Nervous System Lymphoma By Intracerebroventricular Delivery of CD19CAR T Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2161-2161
Author(s):  
Xiuli Wang ◽  
Ryan Urak ◽  
Walter Miriam ◽  
Laura Lim ◽  
Brenda Aguilar ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
Car T Cell ◽  
Car T ◽  
Systemic Lymphoma ◽  
Cns Lymphomas

Abstract Central nervous system lymphoma (CNSL) is a lymphoid malignancy in which tumors from lymph tissue start in the brain, spinal cord, eye, and/or meninges (primary CNSL) or present as a result of metastasis from initial systemic sites to the CNS (secondary CNSL). The most common CNS lymphomas (about 90%) are B-cell lymphomas. The incidence of primary CNS lymphoma has been increasing over the past 20 years. Multifocal lesions are common. CNS lymphomas carry a worse prognosis than systemic lymphoma. Only a few chemotherapeutic drugs can cross and achieve a therapeutic concentration in the CNS. Therefore, effective treatment is limited and the outcome of disease in relapsed or refractory setting is poor. Recent studies show that intraventricular delivery of rituximab in CNS lymphomas is well tolerated. T cell products that are genetically engineered with chimeric antigen receptors (CARs) targeting CD19 have broad application for adoptive therapy of B cell lineage malignancies and have shown tremendous potential in treatment of systemic lymphoma. In all CD19CAR T cell trials, T cell products are administrated intravenously. CD19CAR T cell trafficking in cerebrospinal fluid (CSF) is frequently reported but most if not all protocols exclude patients with active CNS involvement. In this study, we set out to investigate the feasibility and efficacy of the use of CD19CAR T cells to treat CNSL. Methods and Results: Isolated naïve and central memory T cells (Tn/Tmem) were genetically modified with CD19CAR lentivirus and expanded in vitro for 14 days. 0.1x10^6 human B cell lymphoma Daudi cells were injected intracranially into NSG mice. Tumor was allowed to engraft for 5 days. We administered CD19CAR T cells via three different delivery routes: intracranial local infusion with 1x10^6 CD19CAR T cells (i.c), intracerebroventricular (i.c.v) administration with 1x10^6 cells to bypass the blood-brain barrier and target tumor throughout the entire CNS, and intravenous injection (i.v) with 3x10^6 cells. We repeatedly observed in 2 separate experiments (N=5 mice in each experiment) that both a single i.c infusion and a single i.c.v delivery of CD19CAR T cells were able to completely eradicated CNS lymphoma in all mice by day 14 post CAR T cell infusion; and that a single dose of i.v infusion induced significant anti-CNSL activity with a slightly delayed response as compared to i.c and i.c.v treatment and all mice achieved complete remission 21 days post T cell infusion. CAR T cells were detected in peripheral blood obtained from retro-orbital bleeding, not only in the i.v treated mice, but also in i.c.v treated mice 28 days after CAR T cell infusion, suggesting that i.c.v not only controls CNSL but may also play a role in immune surveillance for systemic tumors. To confirm this, we established an NSG CNS B cell lymphoma model by also inoculating subcutaneous tumors on the animal's flank, 3 weeks prior to i.c tumor injection into the same mouse. CD19CAR T cells were delivered via i.c.v 5 days after i.c. tumor injection. CAR T cell injection resulted in complete remission of both the brain tumor and the flank tumor 14 days after CAR T cell administration. In conclusion,intracerebroventricular delivery of CD19CAR T cells is a promising and feasible therapeutic approach for both primary central nervous system lymphoma and systemic lymphoma with concurrent CNS involvement. Disclosures No relevant conflicts of interest to declare.

CAR-T cell therapy in primary central nervous system lymphoma (PCNSL): the clinical experience of the French LOC network

Blood ◽  
2021 ◽  
Author(s):  
Marion Alcantara ◽  
Caroline Houillier ◽  
Marie Blonski ◽  
Marie-Thérèse Rubio ◽  
Lise Willems ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Cell ◽  
Cell Therapy ◽  
Clinical Experience ◽  
Central Nervous System Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2503
Author(s):  
Philipp Karschnia ◽  
Jens Blobner ◽  
Nico Teske ◽  
Florian Schöberl ◽  
Esther Fitzinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cns Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cns Lymphomas

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphoma and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.

scholarly journals The Cerebroventricular Environment Reprograms Locally Infused CAR T Cells for Superior Activity Against Both CNS and Systemic B Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 965-965 ◽  
Author(s):  
Xiuli Wang ◽  
Christian Huynh ◽  
Ryan Urak ◽  
Miriam Walter ◽  
Lihong Weng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cns Lymphoma ◽  
Cns Disease ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Systemic Lymphoma

Abstract Central nervous system lymphoma (CNSL) is a lymphoid malignancy in which tumors from lymph tissue start in the brain, spinal cord, eyes, and/or meninges (primary CNSL) or present as a result of metastasis from initial systemic sites to the CNS (secondary CNSL). The incidence of primary CNS lymphoma has been increasing over the past 20 years. CNS lymphomas carry a worse prognosis than systemic lymphoma, and therefore, effective treatment is urgently needed for CNS disease. T cells that are genetically engineered with chimeric antigen receptors (CAR) targeting CD19 have broad applications in adoptive therapy of B cell malignancies and have shown tremendous potential in the treatment of systemic lymphoma. During the early phase of CD19-CAR T cell studies, most if not all protocols excluded patients with active CNS involvement. In all CD19-CAR T cell trials, T cell products are administrated intravenously. Systemic CD19-CAR T administration for ALL and DLBCL has resulted in complete remission of concurrent CNS disease. CD19-CAR T cell trafficking to the cerebrospinal fluid (CSF) is frequently reported; however, there has been no evidence thus far to indicate that CAR T cells in CSF are related to neurotoxicity. Therefore, an increasing number of CD19-CAR T cell trial protocols no longer exclude patients with active CNS lymphoma involvement. Based on the success of CD19-CAR T cell therapy in ALL and lymphoma, we aimed to translate this strategy toward a more effective therapy for CNS B cell disease. Methods and Results: Isolated naïve and central memory T cells were genetically modified with CD19-CAR lentivirus and expanded in vitro for 14 days. A mouse model with both CNS and systemic lymphoma in the same animal was established by simultaneously engrafting Daudi cells (human B cell lymphoma) intracranially and subcutaneously into NSG mice. We then administered 2x10^6 CD19-CAR T cells via two delivery routes: intracerebroventricular (i.c.v.) to bypass the blood-brain barrier and target tumor throughout the entire CNS, and intravenous injection (i.v.). We repeatedly observed that a single i.c.v. infusion was capable of completely eradicating CNS lymphoma and systemic lymphoma in all mice by day 14 post CAR T cell infusion and 100% of mice remained tumor free for 300 days until the termination of the experiment. In contrast, a single delivery of CD19-CAR T cells via i.v. infusion resulted in a noticeably delayed antitumor activity with complete remissions only observed approximately 40 days post CAR T cell treatment. Eventually, the tumors relapsed and all i.v. treated mice died before day 180 (Figure 1). T cell trafficking experiments demonstrated that i.c.v. CAR T cells are able to efficiently migrate to the periphery, home to systemic tumor locations, and dramatically expand outside the CNS. We were able to detect CAR T cells in the blood, bone marrow, and spleens of mice that received i.c.v. therapy at 300 days post CAR T cell treatment. These persisting T cells are CD4 dominant and express high levels of CD28 with a broad TCR repertoire. The persisting T cells also maintain anti-tumor functionality and are able to resist tumor re-challenge. Further mechanistic studies indicate that factors within the CSF are able to reprogram i.c.v. infused CAR T cells and upregulate genes that are related to memory function. In conclusion, our studies suggest that CAR T cells administrated via i.c.v. and nurtured by CSF exhibit better efficacy, expansion, and persistence, resulting in disease elimination. More interestingly, i.c.v. delivered CAR T cells efficiently traffic beyond the CNS to the periphery and completely eradicate systemic tumors in the same mouse. This study is the first to demonstrate that locally delivered CAR T cells are capable of efficiently treating both systemic lymphoma and concurrent CNS disease, which can lower the risk of cytokine release syndrome and avoid toxicities derived from lymphodepletion and systemic infusion of CAR T cells. Disclosures Wang: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Budde:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

scholarly journals Sequential CD19/22 CAR T-cell immunotherapy following autologous stem cell transplantation for central nervous system lymphoma

2021 ◽  
Vol 11 (7) ◽  
Author(s):  
Jiaying Wu ◽  
Fankai Meng ◽  
Yang Cao ◽  
Yicheng Zhang ◽  
Xiaojian Zhu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Stem Cell ◽  
T Cell ◽  
Complete Remission ◽  
Central Nervous System Lymphoma ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
T Cell Immunotherapy

AbstractChimeric antigen receptor (CAR) T-cell immunotherapy following autologous stem cell transplantation (ASCT) is a promising method for refractory or relapsed multiple myeloma, but explicit data for central nervous system lymphoma (CNSL) are lacking. Here, we treated 13 CNSL patients with ASCT sequential CD19/22 CAR T-cell infusion and simultaneously evaluated the clinical efficacy and toxicity. The 13 CNSL patients analyzed included four primary CNSL and nine secondary CNSL patients. Patients 1 and 10, who had complete remission status before enrollment, maintained clinical efficacy without recurrence. Nine of the remaining 11 patients responded to our protocol with a median durable time of 14.03 months, and the overall response and complete remission rate were 81.81% and 54.55%, respectively. No patient suffered grades 3–4 cytokine-release syndrome (CRS), and only patient 10 experienced severe immune effector cell-associated neurotoxicity syndrome (ICANS). In addition, increases in serum ferritin and interleukin-6 levels were often accompanied by CRS and ICANS. After a median follow-up time of 14.20 months, the estimated 1-year progression-free survival and overall survival rates were 74.59% and 82.50%, respectively. Sequential CD19/22 CAR T-cell immunotherapy following ASCT as a novel method for CNSL appears to have encouraging long-term efficacy with relatively manageable side effects.

scholarly journals Adoptive Immunotherapy beyond CAR T-Cells

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 743
Author(s):  
Aleksei Titov ◽  
Ekaterina Zmievskaya ◽  
Irina Ganeeva ◽  
Aygul Valiullina ◽  
Alexey Petukhov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Solid Tumors ◽  
Adoptive Immunotherapy ◽  
Γδ T Cells ◽  
Car T Cells ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T

Adoptive cell immunotherapy (ACT) is a vibrant field of cancer treatment that began progressive development in the 1980s. One of the most prominent and promising examples is chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of B-cell hematologic malignancies. Despite success in the treatment of B-cell lymphomas and leukemia, CAR T-cell therapy remains mostly ineffective for solid tumors. This is due to several reasons, such as the heterogeneity of the cellular composition in solid tumors, the need for directed migration and penetration of CAR T-cells against the pressure gradient in the tumor stroma, and the immunosuppressive microenvironment. To substantially improve the clinical efficacy of ACT against solid tumors, researchers might need to look closer into recent developments in the other branches of adoptive immunotherapy, both traditional and innovative. In this review, we describe the variety of adoptive cell therapies beyond CAR T-cell technology, i.e., exploitation of alternative cell sources with a high therapeutic potential against solid tumors (e.g., CAR M-cells) or aiming to be universal allogeneic (e.g., CAR NK-cells, γδ T-cells), tumor-infiltrating lymphocytes (TILs), and transgenic T-cell receptor (TCR) T-cell immunotherapies. In addition, we discuss the strategies for selection and validation of neoantigens to achieve efficiency and safety. We provide an overview of non-conventional TCRs and CARs, and address the problem of mispairing between the cognate and transgenic TCRs. Finally, we summarize existing and emerging approaches for manufacturing of the therapeutic cell products in traditional, semi-automated and fully automated Point-of-Care (PoC) systems.

scholarly journals T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma

Rare Tumors ◽  
2015 ◽  
Vol 7 (4) ◽  
pp. 160-162 ◽  
Author(s):  
Pooja Advani ◽  
Jason Starr ◽  
Abhisek Swaika ◽  
Liuyan Jiang ◽  
Yushi Qiu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals 221 CRISPR screen identifies loss of IFNγR signaling and downstream adhesion as a resistance mechanism to CAR T-cell cytotoxicity in solid but not liquid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A234-A234
Author(s):  
Rebecca Larson ◽  
Michael Kann ◽  
Stefanie Bailey ◽  
Nicholas Haradhvala ◽  
Kai Stewart ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Solid Tumors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BackgroundChimeric Antigen Receptor (CAR) therapy has had a transformative impact on the treatment of hematologic malignancies1–6 but success in solid tumors remains elusive. We hypothesized solid tumors have cell-intrinsic resistance mechanisms to CAR T-cell cytotoxicity.MethodsTo systematically identify resistance pathways, we conducted a genome-wide CRISPR knockout screen in glioblastoma cells, a disease where CAR T-cells have had limited efficacy.7 8 We utilized the glioblastoma cell line U87 and targeted endogenously expressed EGFR with CAR T-cells generated from 6 normal donors for the screen. We validated findings in vitro and in vivo across a variety of human tumors and CAR T-cell antigens.ResultsLoss of genes in the interferon gamma receptor (IFNγR) signaling pathway (IFNγR1, JAK1, JAK2) rendered U87 cells resistant to CAR T-cell killing in vitro. IFNγR1 knockout tumors also showed resistance to CAR T cell treatment in vivo in a second glioblastoma line U251 in an orthotopic model. This phenomenon was irrespective of CAR target as we also observed resistance with IL13Ralpha2 CAR T-cells. In addition, resistance to CAR T-cell cytotoxicity through loss of IFNγR1 applied more broadly to solid tumors as pancreatic cell lines targeted with either Mesothelin or EGFR CAR T-cells also showed resistance. However, loss of IFNγR signaling did not impact sensitivity of liquid tumor lines (leukemia, lymphoma or multiple myeloma) to CAR T-cells in vitro or in an orthotopic model of leukemia treated with CD19 CAR. We isolated the effects of decreased cytotoxicity of IFNγR1 knockout glioblastoma tumors to be cancer-cell intrinsic because CAR T-cells had no observable differences in proliferation, activation (CD69 and LFA-1), or degranulation (CD107a) when exposed to wildtype versus knockout tumors. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell adhesion pathways compared to wildtype glioblastoma cells after exposure to CAR T-cells. We found that loss of IFNγR1 reduced CAR T-cell binding avidity to glioblastoma.ConclusionsThe critical role of IFNγR signaling for susceptibility of solid tumors to CAR T-cells is surprising given that CAR T-cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumors, IFNγR signaling was required for sufficient adhesion of CAR T-cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumors differ in their interactions with CAR T-cells and suggests that enhancing T-cell/tumor interactions may yield improved responses in solid tumors.AcknowledgementsRCL was supported by T32 GM007306, T32 AI007529, and the Richard N. Cross Fund. ML was supported by T32 2T32CA071345-21A1. SRB was supported by T32CA009216-38. NJH was supported by the Landry Cancer Biology Fellowship. JJ is supported by a NIH F31 fellowship (1F31-MH117886). GG was partially funded by the Paul C. Zamecnik Chair in Oncology at the Massachusetts General Hospital Cancer Center and NIH R01CA 252940. MVM and this work is supported by the Damon Runyon Cancer Research Foundation, Stand Up to Cancer, NIH R01CA 252940, R01CA238268, and R01CA249062.ReferencesMaude SL, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439–448.Neelapu SS, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531–2544.Locke FL, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. The Lancet Oncology 2019;20:31–42.Schuster SJ, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545–2554.Wang M, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2020;382:1331–1342.Cohen AD, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest 2019;129:2210–2221.Bagley SJ, et al. CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Neuro-oncology 2018;20:1429–1438.Choi BD, et al. Engineering chimeric antigen receptor T cells to treat glioblastoma. J Target Ther Cancer 2017;6:22–25.Ethics ApprovalAll human samples were obtained with informed consent and following institutional guidelines under protocols approved by the Institutional Review Boards (IRBs) at the Massachusetts General Hospital (2016P001219). Animal work was performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) (2015N000218 and 2020N000114).

scholarly journals Absolute lymphocyte count proliferation kinetics after CAR T-cell infusion impact response and relapse

2021 ◽  
Vol 5 (8) ◽  
pp. 2128-2136
Author(s):  
Sophia Faude ◽  
Jane Wei ◽  
Kavitha Muralidharan ◽  
Xiaoming Xu ◽  
Gerald Wertheim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Lymphocyte Count ◽  
Absolute Lymphocyte Count ◽  
Rapid Expansion ◽  
Proliferation Kinetics ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract CD19-directed chimeric antigen receptor (CAR) T cells show characteristic proliferation kinetics after infusion that correlate with response. Clearance of circulating disease, B-cell aplasia (BCA), and cytokine release syndrome (CRS) are used to observe CAR T-cell function, given the lack of commercial CAR T-cell measurement assays. We investigated the utility of common hematology laboratory parameters in 166 patients with B-cell acute lymphoblastic leukemia (B-ALL) who were treated with CAR T-cell therapy targeting CD19. CAR T-cell infusion was followed by disappearance of circulating blasts in 86% of patients at a median of 6 days. After a lag phase, there was a rapid expansion in absolute lymphocyte count (ALC) in the second week that coincided with the appearance of atypical lymphocytes. The expansion phase was followed by a contraction phase with a concomitant decrease in atypical lymphocytes. In vitro CAR T-cell studies showed similar kinetics and morphological changes. Peak ALC and overall expansion was greater in sustained responders compared with that in nonresponders. Patients with early loss of BCA and those with eventual CD19+ minimal residual disease/relapse showed lower overall lymphocyte expansion compared with the controls. Pleomorphic lymphocytosis was noted in the cerebrospinal fluid at post-CAR time points. We conclude that lymphocyte counts and differential can also be used to evaluate CAR T-cell expansion after infusion, along with BCA and CRS. This is the first report to characterize the morphology of CAR T cells and determine the utility of lymphocyte kinetics.

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