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 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 GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells

2019 ◽  
Vol 11 (485) ◽  
pp. eaau7746 ◽  
Author(s):  
Eric L. Smith ◽  
Kim Harrington ◽  
Mette Staehr ◽  
Reed Masakayan ◽  
Jon Jones ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T

Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell–derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.

scholarly journals Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

2020 ◽  
Author(s):  
Eugenia Zah ◽  
Eunwoo Nam ◽  
Vinya Bhuvan ◽  
Uyen Tran ◽  
Brenda Y. Ji ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

ABSTRACTChimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies but also demonstrated marked vulnerability to antigen escape and tumor relapse. Here, we report the rational design and systematic optimization of bispecific CAR-T cells with robust activity against multiple myeloma (MM), including heterogeneous MM that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit significantly higher CAR expression levels and greater antigen-stimulated proliferation compared to T cells that co-express individual BCMA and CS1 CARs. Compared to single-input BCMA- or CS1-targeting CAR-T cells, BCMA/CS1 bispecific CAR-T cells significantly prolong the survival of animals bearing heterogeneous MM tumors. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, but CAR-T cell treatment alone was able to achieve durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

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 Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies

Blood ◽  
2020 ◽  
Author(s):  
Jordan Gauthier ◽  
Evandro D. Bezerra ◽  
Alexandre V. Hirayama ◽  
Salvatore Fiorenza ◽  
Alyssa Sheih ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Severe Toxicity ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

Clinical Responses In Patients Infused With T Lymphocytes Redirected To Target κ-Light Immunoglobulin Chain

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 506-506 ◽  
Author(s):  
Carlos A. Ramos ◽  
Barbara Savoldo ◽  
Enli Liu ◽  
Adrian P. Gee ◽  
Zhuyong Mei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Light Chain ◽  
Stable Disease ◽  
Research Funding ◽  
B Cell Malignancies ◽  
Car T Cells ◽  
Car T

Abstract Adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, causes sustained depletion of normal B cells and consequent severe hypogammaglobulinemia. In order to target B-cell malignancies more selectively, we exploited the clonal restriction of mature B-cell malignancies, which express either a κ or a λ-light immunoglobulin (Ig) chain. We generated a CAR specific for κ-light chain (CAR.κ) to selectively target κ+ lymphoma/leukemia cells, while sparing the normal B cells expressing the reciprocal λ-light chain, thus minimizing the impairment of humoral immunity. After preclinical validation, we designed a phase I clinical trial in which patients with refractory/relapsed κ+ non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) are infused with autologous T cells expressing a CAR.κ that includes a CD28 costimulatory domain. The protocol also included patients with multiple myeloma with the aim of targeting putative myeloma initiating cells. Three dose levels (DL) are being assessed, with escalation determined by a continual reassessment method: 0.2 (DL1), 1 (DL2) and 2 (DL3) ×108 T cells/m2. Repeat infusions are allowed if there is at least stable disease after treatment. End points being evaluated include safety, persistence of CAR+T cells and antitumor activity. T cells were generated for 13 patients by activating autologous PBMC with immobilized OKT3 (n=5) or CD3/CD28 monoclonal antibodies (n=8). In 2 patients with >95% circulating leukemic cells, CD3 positive selection was performed using CliniMACS. After transduction, T cells (1.2×107±0.5×107) were expanded ex vivo for 18±4 days in the presence of interleukin (IL)-2 to reach sufficient numbers for dose escalation. CAR expression was 81%±13% by flow cytometry (74,112±23,000 transgene copy numbers/mg DNA). Products were composed predominantly of CD8+ cells (78%±10%), with a small proportion of naïve (5±4%) and memory T cells (17%±12%). CAR+ T cells specifically targeted κ+ tumors as assessed by 51Cr release assays (specific lysis 79%±10%, 20:1 E:T ratio) but not κ–tumors (11%±7%) or the NK-sensitive cell line K562 (26%±13%). Ten patients have been treated: 2 on DL1, 3 on DL2 and 5 on DL3. Any other treatments were discontinued at least 4 weeks prior to T-cell infusion. Patients with an absolute leukocyte count >500/µL received 12.5 mg/kg cyclophosphamide 4 days before T-cell infusion to induce mild lymphopenia. Infusions were well tolerated, without side effects. Persistence of infused T cells was assessed in blood by CAR.κ-specific Q-PCR assay and peaked 1 to 2 weeks post infusion, remaining detectable for 6 weeks to 9 months. Although the CAR contained a murine single-chain variable fragment (scFv), we did not detect human anti-mouse antibodies following treatment and CAR.κ+T cell expansion continued to be observed even after repeated infusions. We detected modest (<20 fold) elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells, but systemic inflammatory response syndrome (cytokine storm) was absent. No new-onset hypogammaglobulinemia was observed. All 10 patients are currently evaluable for clinical response. Of the patients with relapsed NHL, 2/5 entered complete remission (after 2 and 3 infusions at dose level 1 and 3, respectively), 1/5 had a partial response and 2 progressed; 3/3 patients with multiple myeloma have had stable disease for 2, 8 and 11 months, associated with up to 38% reduction in their paraprotein; and 2/2 patients with CLL progressed before or shortly after the 6-week evaluation. In conclusion, our data indicate that infusion of CAR.κ+ T cells is safe at every DL and can be effective in patients with κ+ lymphoproliferative disorders. Disclosures: Savoldo: Celgene: Patents & Royalties, Research Funding. Rooney:Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

Therapy of B Cell Malignancies with CD19-Specific Chimeric Antigen Receptor-Modified T Cells of Defined Subset Composition

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 384-384 ◽  
Author(s):  
Cameron J Turtle ◽  
Daniel Sommermeyer ◽  
Carolina Berger ◽  
Michael Hudecek ◽  
David M Shank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Research Funding ◽  
T Cell Subsets ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Abstract BACKGROUND: The adoptive transfer of CD19-specific chimeric antigen receptor-modified (CD19 CAR) T cells is a promising strategy for treating patients with CD19+ B cell acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). Dramatic responses have been observed in a subset of patients receiving CD19 CAR T cell therapy, and prior studies suggest that persistence of transferred T cells may correlate with the extent of tumor regression. The use of unselected T cells to prepare CAR T cells results in variation in the phenotypic composition of the infused product in individual patients, making it difficult to determine whether particular T cell subsets contribute to efficacy and/or toxicity. Studies in our lab demonstrated that genetically modified effector T cells derived from purified T cell subsets differ in the capacity to persist in vivo after adoptive transfer, and that a combination of CAR-modified CD8+ central memory (TCM) and CD4+ T cells provides optimal antitumor activity in tumor xenograft models. Based on these data, we designed the first clinical trial in which patients with CD19+ B cell malignancies receive CD19 CAR T cells comprised of a defined composition of CD8+ TCM and CD4+T cells engineered to express a CD19 CAR. METHODS: Patients with relapsed or refractory CD19+ ALL, CLL or NHL are eligible for this phase I/II study. CD8+ TCM and CD4+ T cells were separately enriched by immunomagnetic selection from a leukapheresis product from each patient, and cryopreserved. The CD8+ TCM and CD4+ T cells were stimulated in independent cultures with anti-CD3/anti-CD28 paramagnetic beads, and transduced with a lentivirus encoding the murine FMC63 anti-CD19 scFv, 4-1BB and CD3 zeta signaling domains. After in vitro expansion, the cell product for infusion was formulated in a 1:1 ratio of CD4+:CD8+ CAR+ T cells. A truncated non-functional human epidermal growth factor receptor (EGFRt) encoded in the transgene cassette allowed identification of transgene-expressing T cells by flow cytometry. Lymphodepleting chemotherapy was administered followed by infusion of EGFRt+ CAR T cells at one of three dose levels (2 x 105 EGFRt+ cells/kg, 2 x 106 EGFRt+ cells/kg, 2 x 107 EGFRt+cells/kg). RESULTS: Twenty patients with relapsed or refractory ALL (n = 9), NHL (n = 10) or CLL (n = 1), including those who failed prior autologous (n = 4) or allogeneic (n = 4) stem cell transplant have been treated on the trial. Fifteen of 20 treated patients received a product that conformed to the prescribed CD8+ T­CM:CD4 composition. Five patients received a product manufactured using a modified strategy either due to low blood lymphocyte counts (n = 3) or due to failure to propagate T cells in culture (n = 2). CD8+ TCM and CD4+ T cells have been isolated from 12 additional patients and cryopreserved for therapy. Patients have been treated at all three dose levels without acute infusional toxicity. Severe cytokine release syndrome (sCRS) consisting of fever, hypotension, and reversible neurotoxicity associated with elevated serum IFN-γ and IL-6 was only observed in ALL patients with a high tumor burden. One ALL patient treated at the highest cell dose died of complications associated with sCRS. None of the NHL patients had sCRS. Of patients who are >6 weeks after CD19 CAR T cell therapy, best responses included complete (n=1) or partial (n=5) remission in 6/9 patients with NHL and complete remission in 5/7 patients with ALL. Both CD4+ and CD8+ CAR-T cells expanded in vivo and could be detected in blood, marrow and CSF. The peak level and duration of persistence of both CD4+ and CD8+ EGFRt+ T cells were associated with clinical response. TCRBV gene sequencing of flow sorted CD4+ and CD8+ EGFRt+CAR T cells from 2 patients showed that proliferating CAR T cells were polyclonal. A subset of NHL patients in whom CAR T cells became undetectable developed a T cell immune response to sequences in the murine CD19-specific scFv component of the CAR transgene. CONCLUSION: Adoptive immunotherapy with CD19 CAR T cells of defined subset composition is feasible and safe in a majority of heavily pretreated patients with refractory B cell malignancies and has potent anti-tumor activity. Persistence of CAR-T cells may be limited in some patients by transgene product immunogenicity. Data from this ongoing clinical trial will be updated at the meeting. Disclosures Turtle: Juno Therapeutics: Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Hudecek:Juno Therapeutics: Patents & Royalties. Jensen:Juno: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Riddell:Juno Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Maloney:Juno Therapeutics: Research Funding.

scholarly journals Iomab with Adoptive Cellular Therapy (Iomab-ACT): A Pilot Study of 131-I Apamistamab Followed By CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4810-4810
Author(s):  
Mark B. Geyer ◽  
Briana Cadzin ◽  
Elizabeth Halton ◽  
Peter Kane ◽  
Brigitte Senechal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Research Funding ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Autologous CD19-targeted chimeric antigen receptor-modified (CAR) T-cell therapy leads to complete responses (CR) in patients (pts) with (w/) relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL, &gt;80% CR rate) and diffuse large B-cell lymphoma (DLBCL, ~40-55% CR rate). However, following fludarabine/cyclophosphamide (Flu/Cy) conditioning and CAR T-cell therapy w/ a CD28 costimulatory domain (e.g. 19-28z CAR T-cells), rates of grade ≥3 ICANS and grade ≥3 cytokine release syndrome (CRS) in pts w/ R/R DLBCL and morphologic R/R B-ALL exceed 30%. CRS and ICANS are associated w/ considerable morbidity, including increased length of hospitalization, and may be fatal. Host monocytes appear to be the major reservoir of cytokines driving CRS and ICANS post-CAR T-cell therapy (Giavradis et al. and Norelli et al., Nature Medicine, 2018). Circulating monocytic myeloid-derived suppressor cells (MDSCs) may also blunt efficacy of 19-28z CAR T-cells in R/R DLBCL (Jain et al., Blood, 2021). The CD45-targeted antibody radioconjugate (ARC) 131-I apamistamab is being investigated at myeloablative doses as conditioning prior to hematopoietic cell transplantation in pts w/ R/R acute myeloid leukemia. However, even at low doses (4-20 mCi), transient lymphocyte and blast reduction are observed. Preclinical studies in C57BL/6 mice demonstrate low-dose anti CD45 radioimmunotherapy (100 microCi) transiently depletes &gt;90% lymphocytes, including CD4/CD8 T-cells, B-cells, NK cells, and T-regs, as well as splenocytes and MDSCs, w/ negligible effect on bone marrow (BM) hematopoietic stem cells (Dawicki et al., Oncotarget, 2020). We hypothesized a higher, yet nonmyeloablative dose of 131-I apamistamab may achieve more sustained, but reversible depletion of lymphocytes and other CD45 + immune cells, including monocytes thought to drive CRS/ICANS. We additionally hypothesized this approach (vs Flu/Cy) prior to CAR T-cell therapy would promote CAR T-cell expansion while reducing CSF levels of monocyte-derived cytokines (e.g. IL-1, IL-6, and IL-10), thus lowering the risk of severe ICANS (Fig 1A). Study design and methods: We are conducting a single-institution pilot study of 131-I apamistamab in lieu of Flu/Cy prior to 19-28z CAR T-cells in adults w/ R/R BALL or DLBCL (NCT04512716; Iomab-ACT); accrual is ongoing. Pts are eligible for leukapheresis if they are ≥18 years-old w/ R/R DLBCL (de novo or transformed) following ≥2 chemoimmunotherapy regimens w/ ≥1 FDG-avid measurable lesion or B-ALL following ≥1 line of multi-agent chemotherapy (R/R following induction/consolidation; prior 2 nd/3 rd gen TKI required for pts w/ Ph+ ALL) w/ ≥5% BM involvement and/or FDG-avid extramedullary disease, ECOG performance status 0-2, and w/ appropriate organ function. Active or prior CNS disease is not exclusionary. Pts previously treated w/ CD19-targeted CAR T-cell therapy are eligible as long as CD19 expression is retained. See Fig 1B/C: Post-leukapheresis, 19-28z CAR T-cells are manufactured as previously described (Park et al., NEJM, 2018). Bridging therapy is permitted at investigator discretion. Thyroid blocking is started ≥48h pre-ARC. 131-I apamistamab 75 mCi is administered 5-7 days pre-CAR T-cell infusion to achieve total absorbed marrow dose ~200 cGy w/ remaining absorbed dose &lt;25 cGy at time of T-cell infusion. 19-28z CAR T-cells are administered as a single infusion (1x10 6/kg, B-ALL pts; 2x10 6/kg, DLBCL pts). The primary objective is to determine safety/tolerability of 131-I apamistamab 75 mCi given prior to 19-28z CAR T-cells in pts w/ R/R B-ALL/DLBCL. Secondary objectives include determining incidence/severity of ICANS and CRS, anti-tumor efficacy, and 19-28z CAR T-cell expansion/persistence. Key exploratory objectives include describing the cellular microenvironment following ARC and 19-28z CAR T-cell infusion using spectral cytometry, as well as cytokine levels in peripheral blood and CRS. The trial utilizes a 3+3 design in a single cohort. If dose-limiting toxicity (severe infusion-related reactions, treatment-resistant severe CRS/ICANS, persistent regimen-related cytopenias, among others defined in protocol) is seen in 0-1 of the first 3 pts treated, then up to 6 total (up to 3 additional) pts will be treated. We have designed this study to provide preliminary data to support further investigation of CD45-targeted ARCs prior to adoptive cellular therapy. Figure 1 Figure 1. Disclosures Geyer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Research Funding; Amgen: Research Funding. Geoghegan: Actinium Pharmaceuticals, Inc: Current Employment. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Ludwig: Actinium Pharmaceuticals, Inc: Current Employment. Pandit-Taskar: Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Clarity Pharma: Research Funding; Illumina: Consultancy, Honoraria; ImaginAb: Consultancy, Honoraria, Research Funding; Ymabs: Research Funding; Progenics: Consultancy, Honoraria; Medimmune/Astrazeneca: Consultancy, Honoraria; Actinium Pharmaceuticals, Inc: Consultancy, Honoraria; Janssen: Research Funding; Regeneron: Research Funding. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. OffLabel Disclosure: 131-I apamistamab and 19-28z CAR T-cells are investigational agents in treatment of ALL and DLBCL

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.

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