Chimeric Antigen Receptor T-cell Cells Research Articles

Interleukin Inhibitors in Cytokine Release Syndrome and Neurotoxicity Secondary to CAR-T Therapy.

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an innovative therapeutic option for addressing certain recurrent or refractory hematological malignancies. However, CAR-T cells also cause the release of pro-inflammatory cytokines that lead to life-threatening cytokine release syndrome and neurotoxicity. Objective: To study the efficacy of interleukin inhibitors in addressing cytokine release syndrome (CRS) and neurotoxicity secondary to CAR-T therapy. Methodology: The authors conducted a bibliographic review in which 10 articles were analyzed. These included cut-off studies, case reports, and clinical trials involving 11 cancer centers and up to 475 patients over 18 years of age. Results: Tocilizumab is the only interleukin inhibitor approved to address CRS secondary to CAR-T therapy due to its efficacy and safety. Other inhibitors, such as siltuximab and anakinra, could be useful in combination with tocilizumab for preventing severe cytokine release and neurotoxicity. In addition, the new specific inhibitors could be effective in mitigating CRS without affecting the cytotoxic efficacy of CAR-T therapy. Conclusion: More lines of research should be opened to elucidate the true implications of these drugs in treating the side effects of CAR-T therapy.

Vaccinations following CAR-T cell therapy: summary of reported cases and state-of-the-art review of current recommendations

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is a modern breakthrough technology used in the treatment of B-lineage lymphoid malignancies. These malignancies include acute lymphoblastic leukemia, non-Hodgkin lymphoma, and plasma cell disorders. CAR-T therapy combines cellular therapy, gene therapy, and individualized therapy. The objective of this paper was to review the latest clinical knowledge, and summarize the reported data pertaining to vaccinations in patients after CAR-T therapy. Material and methods: We carried out a review of published original studies as indexed in PubMed, and a review of abstracts presented during major hematology meetings. Results: Overall, 22 original studies were reviewed and considered suitable for analysis regarding the efficacy of vaccinations for patients who had received CAR-T therapy. Data was divided into three groupings: the efficacy of vaccination against coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); the efficacy of vaccination against influenza; and the efficacy of post-CAR-T immunization persistence of vaccination performed before CAR-T therapy. Humoral and cellular response to SARS-CoV-2 vaccination was positive for 36.5% and 72.2% of patients, respectively. The positive response to the influenza vaccine was 40% when administered prior to CAR-T therapy, as opposed to 31% after. Seroprotection for vaccine-preventable infections within 3-6 months after CAR-T was comparable to that of the general population, although it was determined to be less effective against specific pathogens ( S. pneumoniae, B. pertussis, H. influenzae ) in most patients. Conclusions: In cases of incomplete immune reconstitution, there is a high likelihood of a limited response to vaccination. Regarding the SARS-CoV-2/COVID-19 vaccine, T-cell-induced protection is relatively significant. Therefore, B-cell aplasia is not a contraindication for vaccination in CAR-T patients. The consensus of European Society of Blood and Marrow Transplantation/European Hematology Association experts is that vaccination after CAR-T therapy is beneficial in order to reduce the rates of infection, and eventually to improve clinical course.

Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for B-cell acute lymphoblastic leukemia (B-ALL). Although allo-HSCT can be curative for some B-ALL patients, relapse still occurs in some patients following allo-HSCT. Conventional chemotherapies show poor efficacy in B-ALL patients who have relapsed following allo-HSCT. In the past decade, chimeric antigen receptor T-cell (CAR-T) therapy has shown to be efficacious for B-ALL patients. In particular, autologous CD19 CAR-T therapy results in a high remission rate. However, there are challenges in the use of CD19 CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, including the selection of CAR-T cell source for manufacturing, post-CAR-T graft-versus-host disease (GVHD) risk, maintenance of long-term efficacy after remission through CAR-T therapy, and whether a consolidative second transplant is needed. In this review, we describe the current status of CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, the advantages and disadvantages of various CAR-T cell sources, the characteristics and management of GVHD following CAR-T therapy, and the risk factors that may affect long-term efficacy.

Abstract 5182: Population pharmacokinetic modeling of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma

Abstract Objectives: Ciltacabtagene autoleucel (cilta-cel, CARVYKTI, previously JNJ-68284528) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma. Due to the restricted expression of BCMA in normal tissue and expression primarily on late-stage B-cells, plasma cells and malignant B-lineage cells, BCMA is an attractive target for cell therapy for multiple myeloma. The chimeric antigen receptor (CAR) consists of two BCMA-targeting single domain antibodies designed to confer avidity, a CD3ζ signaling domain and a 4-1BB costimulatory domain. The aims of this work were to develop a population pharmacokinetic (PK) model for CAR transgene after single intravenous infusion administration of cilta-cel and to evaluate the effects of subjects’ demographic characteristics and other covariates on CAR transgene PK. Methods: Subjects CAR transgene level in blood, as measured by quantitative polymerase chain reaction (qPCR) were available from 97 subjects in a Phase 1b/2 CARTITUDE-1 study (NCT03548207). A targeted cilta-cel dose of 0.75x106 (range 0.5-1.0x106) CAR-positive viable T-cells/kg body weight was given 5-7 days after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). The data were analyzed by a non-linear mixed effects modeling approach implemented in NONMEM V7.4.3. The population PK model development was based on existing information on CAR T-cell (CAR-T) PK with some modifications. Model qualification was guided by the objective function value, diagnostic plots, standard error of parameters, evaluation of condition number, shrinkage, and visual predictive checks. Results: The PK of cilta-cel following IV infusion was adequately described by a 2-compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of 4 transit compartments with a lag time empirically representing the process from infused CAR-T cell to measurable CAR transgene. The model diagram is shown in Figure 1, consisting of 5 parameters and their respective inter-individual variability (lognormal distribution). The dose was defined as the number of CAR-positive viable T cells infused, and the fitted CAR transgene level (units of copies/μg genomic DNA) observation was the sum of the 2 CAR-T cell compartments. Conclusion: A population PK model has been developed to characterize CAR transgene level of cilta-cel in blood following IV infusion of 0.75x106 (range 0.5-1.0x106) CAR-positive viable T-cells/kg body weight. The developed model is robust and adequate for investigating the covariate effects on CAR transgene level of cilta-cel and enabling subsequent exposure-safety and exposure-efficacy analyses. Citation Format: Liviawati S. Wu, Yaming Su, Claire Li, Wangda Zhou, Carolyn Jackson, Yu-Nien Sun, Honghui Zhou. Population pharmacokinetic modeling of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5182.

Comparisons of Long-Term Survival and Safety of Haploidentical Hematopoietic Stem Cell Transplantation After CAR-T Cell Therapy or Chemotherapy in Pediatric Patients With First Relapse of B-Cell Acute Lymphoblastic Leukemia Based on MRD-Guided Treatment

Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9–89.6) vs. 44.4% (95% CI: 15.4–73.4), p = 0.19 and 84.6% (95% CI: 70.6–98.5) vs. 40.0% (95% CI: 12.7–67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.

Barriers to Chimeric Antigen Receptor T-Cell (CAR-T) Therapies in Clinical Practice.

Chimeric antigen receptor T-cell (CAR-T) therapy is a revolutionary cancer treatment modality where a patient’s own T cells are collected and engineered ex vivo to express a chimeric antigen receptor (CAR). These reprogrammed CAR-T cells, when reinfused into the same patient, stimulate a T-cell mediated immune response against the antigen-expressing malignant cells leading to cell death. The initial results from pivotal clinical trials of CAR-T agents have been promising, leading to multiple approvals in various hematologic malignancies in the relapsed setting, including acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, and, more recently, multiple myeloma. However, since the initial trials and US Food and Drug Administration approvals, there have been significant barriers to the widespread use of this therapy. The barriers to the use of CAR-T therapy include complex logistics, manufacturing limitations, toxicity concerns, and financial burden. This review discusses potential solutions to overcome these barriers in order to make this life-changing therapy widely accessible.

T cells expressing CD5/CD7 bispecific chimeric antigen receptors with fully human heavy-chain-only domains mitigate tumor antigen escape

Bispecific chimeric antigen receptor T-cell (CAR-T) therapies have shown promising results in clinical trials for advanced B-cell malignancies. However, it is challenging to broaden the success of bispecific CAR-T therapies to treat refractory/relapse (r/r) T-cell leukemia/lymphoma because targeting multiple T-cell-expressing antigens leads to exacerbated CAR-T cell fratricide and potential safety concerns. Fully human heavy chain variable (FHVH) antibodies that specifically target CD5 or CD7 were screened and constructed to CD5/CD7 bispecific CARs. A truncated Epidermal growth factor receptor were integrated into CAR constructs to address safety concerns. To tackle the fratricidal issue of CAR-T cells targeting T-cell-pan marker(s), CRISPR/Cas9-based CD5 and CD7 genes knockout were performed before lentiviral transduction of bispecific CARs. Functional comparison between different bispecific CAR structures: tandem CARs and dual CAR were performed in vitro and in vivo to determine the optimal construct suitable for addressing T-cell malignancy antigen escape in clinical setting. Knockout of CD5 and CD7 prevents fratricide of CD5/CD7 bispecific CAR-T cells, and FHVH-derived CD5/CD7 bispecific CAR-T cells demonstrate potent antitumor activity in vitro and in vivo. The fratricide-resistant FHVH-derived CD5/CD7 bispecific CAR-T cells have potent antitumor activity against T-cell malignancies, and tandem CARs are more effective than dual CAR in preventing tumor escape in heterogeneous leukemic cells. The meaningful clinical efficacy and safety of tandem CD5/CD7 CAR-T cells deserve to be explored urgently.

Cytopenia after CAR-T Cell Therapy-A Brief Review of a Complex Problem.

Simple SummaryChimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as a new life-saving treatment modality in patients with relapsed or refractory B-cell malignancies and multiple-myeloma. In this form of therapy, patient’s T-cells are modified by various genetic techniques to express a new receptor that identifies and kills the cancer cells. With increasing use, they present with distinct immune mediated side effects such as cytokine release syndrome (CRS), neurotoxicity, and prolonged cytopenia. While our understanding of CRS and other immune side-effects has increased, prolonged cytopenia post CAR-T infusion remains under-recognized and under-reported. With the focus on prolonged cytopenia in this review, we aim to summarize findings of various clinical trials, postulated mechanisms, and clinical interventions to risk-stratify and manage this clinical entity.Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as an efficacious and life extending treatment modality with high response rates and durable remissions in patients with relapsed and refractory non-Hodgkin lymphoma (NHL), follicular lymphoma, and B-cell acute lymphoblastic leukemia (B-ALL) as well as in other diseases. Prolonged or recurrent cytopenias after CAR-T therapy have increasingly been reported at varying rates, and the pathogenesis of this complication is not yet well-understood but is likely contributed to by multiple factors. Current studies reported are primarily retrospective, heterogeneous in terms of CAR-Ts used and diseases treated, non-uniform in definitions of cytopenias and durations for end points, and vary in terms of recommended management. Prospective studies and correlative laboratory studies investigating the pathophysiology of prolonged cytopenias will enhance our understanding of this phenomenon. This review summarizes knowledge of these cytopenias to date.

The role of CAR-T cell therapy as second line in diffuse large B-cell lymphoma.

For approximately three decades, autologous hematopoietic cell transplantation (auto-HCT) has been the standard of care for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after frontline therapy. This approach is limited due to the intensity of chemotherapy and the proportion of patients who relapse after auto-HCT. Since the approval of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and novel agents, the treatment paradigm for DLBCL has changed remarkably. Anti-CD19 CAR-T therapy was first approved for relapsed DLBCL after two or more previous lines of therapy with long-lasting responses, with over 50% of patients still alive at 5-year follow-up. Here, we discuss recent randomized phase 3 clinical trials using axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in the second-line therapy setting compared with the standard of care in transplant-eligible patients who have DLBCL R/R within 12 months of completing chemo-immunotherapy, potentially changing the treatment algorithm for DLBCL.

Early Dynamics and Depth of Response in Multiple Myeloma Patients Treated With BCMA CAR-T Cells.

Chimeric antigen receptor T-cell (CAR-T) therapy targeted against B-cell maturation antigen (BCMA) in multiple myeloma (MM) has produced rapid responses but many eventually relapse. In light of this new treatment, novel predictors of progression-free survival (PFS) are needed. We performed a single institution analysis of 54 BCMA-CAR-T patients. We analyzed patient’s overall response rate (ORR) by the IMWG criteria, involved serum-free light chains (iFLC), and minimal residual disease testing by next-generation sequencing (MRD-NGS). Between patients who achieved a ≤SD and those who achieved a ≥PR, PFS differed significantly (p < 0.0001); though there was no difference between patients who achieved a ≥CR vs. VGPR/PR (p = 0.2). In contrast, patients who achieved a nonelevated iFLC at 15 days (p < 0.0001, HR = 6.8; 95% CI, 2.7–17.3) or 30 days (p < 0.001, HR = 16.7; 95% CI, 3.9–71.7) had a prolonged PFS compared with those with an elevated iFLC. Patients achieving MRD-NGS less than the detectable limit at a sensitivity of 10−6 had a better PFS than those with detectable disease at 1 month (p = 0.02) and 3 months (p = 0.02). In conclusion, achieving a nonelevated iFLC and an undetectable MRD-NGS quickly were factors that were strongly associated with improved PFS. Further studies are needed to confirm the role of these markers in MM patients receiving CAR-T therapies.

High Dose Fractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (mHyperCVAD) Is an Active Regimen in Heavily Pretreated Relapsed/Refractory Multiple Myeloma, Enabling Access to Experimental Therapies

BackgroundTherapeutic advancements and deeper understanding of disease biology have helped improve the outcomes of multiple myeloma (MM). However, there is no consensus regarding the optimal management of patients whose disease becomes refractory to the three main class of drugs [proteasome inhibitors (PI), immunomodulatory drug (IMiD), and monoclonal antibodies (mab)] or among those presenting with complications secondary to rapidly progressive disease. While chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engagers have yielded high rates of durable responses, access to these therapies in clinical trials is often hindered by high disease burden compromising eligibility. We evaluated the use of a combination of cytotoxic agents (cyclophosphamide, doxorubicin, vincristine, and dexamethasone; mHyperCVAD) in this challenging population.MethodsThis is a retrospective, single center study evaluating the safety/tolerability and efficacy of mHyperCVAD in relapsed and refractory MM (RRMM). The regimen consists of cyclophosphamide 300 mg/m2 IV every 12 hours on D1-4 (total 2400 mg/m2), vincristine 0.4 mg/day IV continuous infusion D1-4 (total 1.6 mg), doxorubicin 9 mg/m2/day IV continuous infusion D1-4 hours (total 36 mg/m2) and dexamethasone 40 mg PO daily D1-4. Adult patients with RRMM were included if they received ≥1 cycle of mHyperCVAD between 2019-2021. Patients with primary plasma cell leukemia were excluded. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Patients were censored for progression free survival (PFS) at the last follow-up date if neither progression nor death occurred. All patients received growth factors, and infectious disease prophylaxis per institutional standard. Toxicities were graded using CTCAE v5.0 up to 30 days post therapy.ResultsBetween 1/2019 and 7/2021, 39 patients met the inclusion criteria and received 44 courses of mHyperCVAD (four patients received mHyperCVAD at more than one timepoint). The median age was 54 years (range 32-71), 56% male. 36% patient had ISS stage III disease and 56% had high risk disease [t(4;14), t(14;16), del17p, +1q]. The median lines of therapy prior to mHyperCVAD were 3 (range 1-12) with 93% triple class refractory (refractory to PI, IMID and mab) and 64% penta-refractory (refractory to 2 PI, 2 IMiDs and mab) and 76% had received a prior autologous transplant. The median number of mHyperCVAD cycles per course was 1 (range 1-8). Baseline characteristics are summarized in Table. Eleven courses (25%) were administered as bridge after lymphocyte collection for the manufacture of CAR-T cells and prior to lymphodepletion chemotherapy (100% triple class refractory and 91% penta-refractory) with ORR 18% and DCR 72%. Thirty-three courses (75%) were used as salvage for rapid disease control. The most common toxicities with mHyperCVAD were hematologic (65% grade 3/4 toxicities) with 20% incidence of febrile neutropenia. Four patients died during mHyperCVAD therapy due to rapidly progressive disease and one patient died due to sepsis.For the entire cohort, the ORR is 50% (≥VGPR 30%) with a DCR 82%. Additionally, 39% could proceed with experimental CAR-T cells and/or bispecific T cell engagers. The median progression free survival is 3.6 months, and the median overall survival is 8 months from start of mHyperCVAD with 10.5 months median follow up. The most common cause of death was progressive disease (39%).ConclusionmHyperCVAD is an efficacious cytotoxic chemotherapy regimen which can achieve rapid disease control allowing patients an opportunity to proceed with additional therapies, including investigational agents on clinical trials. It can also be used as an effective bridging strategy among heavily treated, triple class and penta-refractory MM awaiting manufacturing of CAR-T cells with manageable and expected toxicities. [Display omitted] DisclosuresGiri: PackHealth: Research Funding; CareVive: Honoraria, Research Funding. Costa: Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau.

Outcomes of Large B-Cell Lymphoma Patients By Post CAR-T Salvage Regimen at a Single Institution

Introduction:Outcomes of patients with large B-cell lymphoma that relapse after frontline anthracycline based chemotherapy are typically poor, with a 3-year event-free survival of approximately 30% (Gisselbrecht JCO 2010). Chimeric antigen receptor T-cell (CAR-T) therapy represents a breakthrough therapy for these patients, with an overall response rate (ORR) of 83% and a complete response (CR) rate of 58% for axicabtagene ciloleucel (axi-cel) seen in the ZUMA-1 trial, with similar rates for tisagenlecleucel in the JULIET trial (Locke Lancet Oncol 2018; Schuster NEJM 2018). Unfortunately, the majority of patients treated with CAR-T therapy experience disease progression. There is limited data evaluating the best salvage regimen for these patients. Thus, we sought to assess outcomes in large B-cell lymphoma patients with progressive disease post CAR-T cell therapy with the goal of identifying those therapies with optimal outcomes.Methods:A retrospective study was performed on all patients with large B-cell lymphoma undergoing leukapheresis for CAR-T therapy (tisagenlecleucel or axi-cel) at the Ohio State University from December 2017 to January 2021. Patients who died prior to CAR-T infusion were excluded from analysis. Demographics and disease characteristics as well as best response to CAR-T and date of relapse or progression following therapy were collected. First salvage therapy at relapse or progression and response to therapy were also collected, with choice of therapy driven by the treating physician. Patients were divided by salvage regimen into five groups for analysis: checkpoint inhibitor based, lenalidomide based, Bruton Tyrosine Kinase inhibitor (BTKi), chemoimmunotherapy, and other (including small molecular inhibitor, radiation, allogeneic stem cell transplant, antibody drug conjugates, and bispecific antibodies). The primary endpoint was overall survival (OS), which was calculated using Kaplan Meier Curves. Rates of CR and ORR were also assessed.Results:A total of 144 patients underwent leukapheresis for CAR-T cell therapy during the time period; of these patients, 13 died prior to undergoing CAR-T cell infusion and were excluded from analysis. The primary cohort included 131 patients. Median age at the time of T-cell collection was 62 years old (range 23-85) and 61% were male. The majority (50%) had germinal center (GCB) subtype, with 42% non-GCB and subtype unavailable for 8%. A small number (3%) had primary mediastinal B-cell lymphoma. The majority had high-risk disease, with 45% having primary refractory disease, 14.5% double or triple hit, and 81% Ann Arbor stage III or IV at diagnosis. Median prior lines of therapy was 3 (range 0-10). Sixty-six patients received axi-cel and 65 patients received tisagenlecleucel.Forty percent of patients attained a CR, 18% partial response (PR), 3% stable disease (SD), 33% progressive disease (PD), and 6% of patients died prior to disease assessment. For those 76 patients that received a CR or PR to therapy, 43% relapsed post CAR-T and 57% remained in CR at last follow-up. Of those patients who relapsed or progressed post CAR-T, 69% (54/78) patients received additional therapy. The most common therapies utilized were lenalidomide based (35%), BTKi (22%), chemoimmunotherapy (13%), and checkpoint inhibitor based (15%). Other therapies represented 15% of cases and included small molecular inhibitor, radiation, allogeneic stem cell transplant, antibody drug conjugates, and bispecific antibodies (Table 1). Overall response rates and median OS for the groups were 50% and 2.25 years for BTKi, 13% and 0.96 years for checkpoint inhibitor based, 71% and not reached (NR) for chemoimmunotherapy, 47% and 2.4 years for lenalidomide based, and 75% and NR for other (Table 1; Figure 1). Median OS for those patients who did not receive any salvage therapy was 0.19 years.Conclusion:Consistent with prior studies, median OS following relapse post CAR-T therapy was poor, with median OS 0.19 years for patients who did not receive therapy and ranging from 0.96 years to NR for those that did. Rates of CR were highest in patients treated with BTKis. In our series, ORR rate to checkpoint inhibitors was relatively low in contrast to other recently published retrospective reports. Future prospective studies are needed to further assess the optimal therapy for patients who relapse post CAR-T therapy. [Display omitted] DisclosuresBond: Kite/Gilead: Honoraria. Brammer: Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy; Celgene: Research Funding. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

High Effectiveness and Safety of Anti-CD7 CAR T-Cell Therapy in Treating Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL)

BackgroundCompared with the substantial efficacy of chimeric antigen receptor T-cell (CAR-T) therapy that has achieved in B-ALL, whether CAR-T therapy is effective and safe for patients with T-ALL is still being explored in early stage clinical trials. Here, we present outcomes from our phase 1 clinical trial of CD7-targeting CAR-T (CD7CAR) cells therapy for R/R T-ALL (NCT04572308).MethodsPeripheral blood (PB) mononuclear cells were obtained by leukapheresis. T cells were separated and transduced with lentivirus. The second-generation CD7CAR is composed of an anti-CD7 single-chain antibody, a IgG4 hinge region, a CD28TM transmembrane domain, an intracellular co-stimulatory domain of 4-1BB and CD3ζ, and the truncated EGFR protein linked by T2A. All patients received intravenous fludarabine (30 mg/m 2/d) and cyclophosphamide (300 mg/m 2/d) for 3 days prior to CD7CAR infusion.ResultsSeventeen R/R T-ALL patients were enrolled between December 2020 and June 2021. Characteristics of patients are shown in Table 1. Data from 14 patients with a median age of 17 years (range: 3-42 years) were available for evaluation. The rest 3 patients were withdrawn from study within 14 days due to rapid disease progression. High-risk subtype patients enrolled including 1 with Ph-positive T-ALL and 3 with early T-cell precursor (ETP)-ALL. Seven of the 14 patients also had high-risk genotypes, namely SIL-TAL1, EZH2, TP53, RUNX1, BCR-ABL, JAK1 and JAK3. At enrollment, the median percentage of bone marrow (BM) blasts was 11.53% (range: 0.18%-65.03%), and 5 of 14 patients had extramedullary involvements, including optic nerve involvement (N=2), central nervous system leukemia (N=3), diffuse extramedullary involvements (N=2), and bulky lymph nodes in the neck (N=1). Patients were heavily pretreated with a median of 5 prior lines of therapies (range: 3-8 lines) and three relapsed from prior allogeneic hematopoietic stem cell transplantation (allo-HSCT).CD7CAR-T cells were 100% successfully manufactured with a transfection efficiency of 93.8% (range: 59.6%-99.9%). Twelve of 14 participants received bridging chemotherapy. A single dose of CD7CAR-T cells was infused to patients, with 2 receiving a low-dose (0.5x10 5 cells/kg), 11 receiving a medium dose (1-1.5x10 6 cells/kg) and 1 receiving a high-dose (2x10 6 cells/kg).By the data cutoff date (July 12, 2021), the median follow-up time was 105 days (range: 32-206 days, Fig.1A). By day 28 post infusion, 92.9% (13/14) of patients achieved complete remission (CR, N=4) or CR with incomplete hematological recovery (CRi, N=9) in their BM, with all 13 patients achieving minimal residual disease (MRD) negative CR/CRi. Additionally, 4/5 patients with extramedullary involvement also achieved extramedullary remission at a median of day 32 (range: 28-90 days) post infusion. Consolidation allo-HSCT was permitted at the treatment physician's discretion and the patient's preference. A total of 11/14 patients were bridged to consolidation allo-HSCT at a median of 57 days post CD7CAR infusion, of which 9 patients have remained MRD-negative CR/CRi. One patient who had allo-HSCT prior to CD7CAR infusion died following a second haplo-HSCT due to acute graft-versus-host disease. Of the other 3 patients who were not bridged to allo-HSCT, 1 patient relapsed on day 28 due to rapid disease progression after initial CRi on day 14. Thirteen of 14 patients experienced mild CRS (Grade ≤2). One patient had Grade 3 CRS. The median time to onset of CRS was 1 day (range: 0-11 days), with a median duration of 14 days (range: 3-25 days). Neurotoxicity (Grade 1) occurred in only 1 patient.After infusion, the median peak of CAR-T copy number was 2.38 ×10 5copies/µg DNA (range: 0.2-6.67 ×10 5 copies/µg DNA), which occurred on day 20 (range: 10-42 days, Fig.1B). Importantly, CD7CAR persisted well in PB at a median of 52.5 days (range:20-120 days) at last evaluation regardless of transplantation status. Maximum proportion of CD7CAR-T cells proliferation reached 84.95% by flow cytometry (Fig.1C).ConclusionsOur results demonstrate that CD7CAR therapy is safe and highly effective in treating patients with heavily pretreated R/R T-ALL, including those with extramedullary involvements, a history of prior allo-HSCT or with high-risk subtypes. More patients and a longer observation time are needed to further evaluate the potential beneficial advantages and side effects of CD7CAR therapy for T-ALL patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pilot Implementation of Remote Patient Monitoring Program for Outpatient Management of CAR-T Cell Therapy

Pilot Implementation of Remote Patient Monitoring Program for Outpatient Management of CAR-T Cell Therapy

Cost per Responder Analysis to Assess the Value of CAR-T Therapy for Relapsed or Refractory Multiple Myeloma

New classes of therapies have emerged for treating Relapsed or Refractory Multiple Myeloma (RRMM) patients, including chimeric antigen receptor T-cell (CAR-T) therapies targeting the B-cell maturation antigen. While CAR-T therapies are expected to be a more expensive class of treatment compared to chemotherapy, 1 they have been shown to have a high overall response rate (ORR) and progression-free survival (PFS). 2,3 As newer, more innovative RRMM therapies are developed and brought to market, payers will need to balance their higher efficacy and total treatment costs when assessing potential value. To assess the value of RRMM CAR-T therapies (ciltacabtagene autoleucel [cilta-cel] and idecabtagene vicleucel [ide-cel]), we developed a cost per responder (CPR) model that incorporates efficacy and total cost of treatment.In the absence of head-to-head trial data for CAR-T therapies, indirect treatment comparisons (ITCs) can be used to evaluate comparative efficacy, and the results can be used to inform a CPR model. Matching-adjusted indirect comparisons (MAIC) is a form of ITC that involves matching and adjusting a treatment group from a clinical study with individual patient-level data (IPD) available to a comparator for which only summary-level data are available. This method mitigates potential bias arising from differences in patient characteristics between trials and is widely used and accepted in comparative effectiveness research. Unanchored matching adjusted indirect comparison (MAIC) analyses were used to inform the comparative efficacy of cilta-cel versus ide-cel in our CPR model. MAIC results indicated that cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 87.99 [95% confidence interval [CI]: 20.32, 381.01; p < .0001]), complete response or better (≥CR) rate (OR: 5.96 [95% CI: 2.76, 12.88; p < .0001]) and PFS (hazard ratio [HR]: 0.36 [95% CI: 0.22, 0.59; p < .0001]) when compared with ide-cel. 4To adequately capture total treatment costs for each treatment of interest, CPR models should include all costs related to acquisition and delivery of treatment. Relevant costs of CAR-T therapy for RRMM include the cost of apheresis, bridging therapy, costs of CAR-T acquisition and administration, supportive care and monitoring costs, adverse event management costs, and any costs associated with delivery of inpatient or outpatient clinical services.Preliminary results of the CPR analysis indicate that ide-cel is associated with a cost per ORR of approximately $743,000, a cost per CR or better of $1.66 million and a cost per month in PFS of approximately $55,000. Corresponding results for cilta-cel will be generated after the PDUFA date (November 29, 2021), and presented at ASH 2021.In conclusion, CPR models have significant potential to assist payers in evaluating the value of newer, more innovative RRMM therapies by integrating information on both total costs and efficacy.References1 Pagliarulo N. FDA approves first CAR-T cell therapy for multiple myeloma. https://www.biopharmadive.com/news/fda-car-t-multiple-myeloma-approval-bristol-myersbluebird/597438/#:~:text=The%20pharma%2C%20which%20licensed%20the,other%20approve d%20CAR%2DT%20therapies. Published 27 March 2021. Accessed 22 June 2021.2 Munshi NC, Anderson Jr LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-16.3 Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy, in relapsed/refractory multiple myeloma [abstract]. Blood. 2020;136(1 supplement). Abstract 177.4 Martin T, Usmani SZ, Schecter JM, Vogel M, Jackson CC et al. (2021) Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. Curr Med Res Opin 1-10. DisclosuresMartin: Sanofi: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Usmani: Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Joseph: Johnson and Johnson: Current Employment, Current equity holder in publicly-traded company. Crivera: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Valluri: Janssen: Current Employment, Current equity holder in publicly-traded company. Jackson: Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Cohen: Eversana Life Science Services: Current Employment, Other: Eversana Life Science Services was contracted by Janssen to work on this project.. Singh: Eversana Life Science Services: Current Employment, Other: Eversana Life Science Services was contracted by Janssen to work on this project..

ATG-010 Plus Low-Dose Dexamethasone (Sd) in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Received Chimeric Antigen Receptor T-Cell (CAR-T)

Background:There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM. MARCH study, a single arm, Phase 2, registrational study evaluating Sd in Chinese RRMM pts, achieved an overall response rate (ORR) of 29.3% (95% CI: 19.7, 40.4), rejecting the null hypothesis of the study. Given its unique and novel mechanism of action, Sd preserves anti-tumor activity regardless of specific prior therapies. In the MARCH study, encouraging activity was demonstrated in a small group of Chinese RRMM pts previously exposed to CAR-T therapy.Methods:The study enrolled 82 pts previously exposed and refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and last line of therapy. Among them, 10 had received lymphodepleting conditioning followed by CAR-T cell therapy before study screening. ATG-010 (80mg) plus dexamethasone (20mg) was administered orally twice weekly. Response was assessed by an independent review committee.Results:Among 10 pts, 8 were male and 2 were female. Median age was 58.5 years. Median duration from MM initial diagnosis was 5.2 years. A total of 6 pts (60.0%) had high-risk cytogenetic abnormalities, including 4 pts (40.0%) with del (17p). Three pts had baseline plasmacytoma. Five pts (50%) experienced very rapid disease progression as indicated by a median of 46.2% increase of tumor burden from screening to Cycle 1 Day 1. Patients were heavily pre-treated with a median of 9.5 prior regimens (range: 5-12), with 8 receiving more than 6 regimens. Four pts were exposed to daratumumab (triple-class exposure). ORR was 50% including 1 very good partial response and 4 partial responses. Disease control rate defined as SD and above was 70%. Median duration of response was 1.4 months (mo) (95% CI: 0.96, NE). Median progression free survival was 1.9 mo (95% CI: 0.93, 3.74). xx pts (xx%) pts died; median overall survival was not reached, and estimated 12-mo OS rate was 68.6%.Adverse events were consistent with those events previously reported with Sd regimen in RRMM patients. The most common grade≥3 treatment emergent adverse events (TEAEs) included anemia, thrombocytopenia, neutropenia and nausea. Most events were manageable with appropriate supportive care or dose modification. Four pts (40%) experienced TESAEs, including anemia, pneumonia, neutropenia, and upper gastrointestinal hemorrhage. There were no TEAEs leading to treatment discontinuation or death.Conclusions:Sd was able to induce an encouraging response with a manageable safety profile for a group of Chinese RRMM patients desperately needing treatment after failing CAR-T therapy. With the small sample size, further investigation is warranted, including using ATG-010 in combination with other anti-MM therapies to potentially enhance and prolong therapeutic benefit. DisclosuresYu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Comparison of Cilta-cel, an Anti-BCMA CAR-T Cell Therapy, Versus Conventional Treatment in Patients With Relapsed/Refractory Multiple Myeloma

BackgroundIn the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed). Patients and MethodsA dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients. ResultsIn ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods. ConclusionCilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM.

Humanized Anti-CD19 CAR-T Cell Therapy and Sequential Allogeneic Hematopoietic Stem Cell Transplantation Achieved Long-Term Survival in Refractory and Relapsed B Lymphocytic Leukemia: A Retrospective Study of CAR-T Cell Therapy.

Early response could be obtained in most patients with relapsed or refractory B cell lymphoblastic leukemia (R/R B-ALL) treated with chimeric antigen receptor T-cell (CAR-T) therapy, but relapse occurs in some patients. There is no consensus on treatment strategy post CAR-T cell therapy. In this retrospective study of humanized CD19-targeted CAR-T cell (hCART19s) therapy for R/R B-ALL, we analyzed the patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) or received a second hCART19s infusion, and summarized their efficacy and safety. We retrospectively studied 28 R/R B-ALL patients treated with hCART19s in the Affiliated Hospital of Xuzhou Medical University from 2016 to 2020. After the first hCART19s infusion, 10 patients received allo-HSCT (CART+HSCT group), 7 patients received a second hCART19s infusion (CART2 group), and 11 patients did not receive HSCT or a second hCART19s infusion (CART1 group). The safety, efficacy, and long-term survival were analyzed. Of the 28 patients who received hCART19s treatment, 1 patient could not be evaluated for efficacy, and 25 (92.6%) achieved complete remission (CR) with 20 (74.7%) achieving minimal residual disease (MRD) negativity. Seven (25%) patients experienced grade 3-4 CRS, and one died from grade 5 CRS. No patient experienced ≥3 grade ICANS. The incidence of second CR is higher in the CART+HSCT group compared to the CART2 group (100% vs. 42.9%, p=0.015). The median follow-up time was 1,240 days (range: 709–1,770). Significantly longer overall survival (OS) and leukemia-free survival (LFS) were achieved in the CART+HSCT group (median OS and LFS: not reached, p=0.006 and 0.001, respectively) compared to the CART2 group (median OS: 482; median LFS: 189) and the CART1 group (median OS: 236; median LFS: 35). In the CART+HSCT group, the incidence of acute graft-versus-host disease (aGVHD) was 30% (3/10), and transplantation-related mortality was 30% (3/10). No chronic GVHD occurred. Multivariate analysis results showed that blasts ≥ 20% in the bone marrow and MRD ≥ 65.6% are independent factors for inferior OS and LFS, respectively, while receiving allo-HSCT is an independent factor associated with both longer OS and LFS. In conclusion, early allo-HSCT after CAR-T therapy can achieve long-term efficacy, and the adverse events are controllable.

CAR‐T therapy: Prospects in targeting cancer stem cells

Cancer stem cells (CSCs), a group of tumour cells with stem cell characteristics, have the ability of self‐renewal, multi‐lineage differentiation and tumour formation. Since CSCs are resistant to conventional radiotherapy and chemotherapy, their existence may be one of the root causes of cancer treatment failure and tumour progression. The elimination of CSCs may be effective for eventual tumour eradication. Because of the good therapeutic effects without major histocompatibility complex (MHC) restriction and the unique characteristics of CSCs, chimeric antigen receptor T‐cell (CAR‐T) therapy is expected to be an important method to eliminate CSCs. In this review, we have discussed the feasibility of CSCs‐targeted CAR‐T therapy for cancer treatment, summarized current research and clinical trials of targeting CSCs with CAR‐T cells and forecasted the challenges and future direction from the perspectives of toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, and tumour heterogeneity.

The impact of bridging therapy prior to CD19‐directed chimeric antigen receptor T‐cell therapy in patients with large B‐cell lymphoma

In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n=75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P=0·18 and P=0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P=0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P=0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.