Chimeric Antigen Receptor T-cell Treatment Research Articles

Cost effectiveness analysis of CAR-T cell therapy for patients with relapsed/refractory multiple myeloma in China

BackgroundThe landscape of treatment strategies for relapsed/refractory multiple myeloma (RRMM) has dramatically changed due to the emergence of chimeric antigen receptor T (CAR-T) cell therapy. The aim of this study was to evaluate the cost-effectiveness of two CAR-T cell treatments for RRMM patients from the perspective of the Chinese healthcare system.MethodsA Markov model was used to compare currently available salvage chemotherapy with Idecabtagene vicleucel (Ide-cel) and Ciltacabtagene autoleucel (Cilta-cel) for treatment of patients with RRMM. The model was developed based on data from three studies: CARTITUDE-1, KarMMa, and MAMMOTH. The healthcare cost and utility of RRMM patients were collected from a provincial clinical center in China.ResultsIn the base case analysis, 3.4% and 36.6% of RRMM patients were expected to be long-term survivors after 5 years of Ide-cel and Cilta-cel treatment, respectively. Compared to salvage chemotherapy, Ide-cel and Cilta-cel were associated with incremental QALYs of 1.19 and 3.31, and incremental costs of US$140,693 and $119,806, leading to ICERs of $118,229 and $36,195 per QALY, respectively. At an ICER threshold of $37,653/QALY gained, the probability that Ide-cel and Cilta-cel are cost-effective were estimated to be 0% and 72%, respectively. With younger target people entering the model, and a partitioned survival model in scenario analysis, the ICERs of Cilta-cel and Ide-cel changed rather mildly and their cost-effectiveness results were the same as base analysis.ConclusionsBased on the willingness-to-pay of 3-times China’s per capita GDP in 2021, Cilta-cel was considered to be a more cost-effective option compared to salvage chemotherapy for RRMM in China, while Ide-cel was not.

Delayed Onset ICANS Leading to Bilateral Cranial Neuropathies: Two Case Reports (P12-13.005)

<h3>Objective:</h3> To describe two cases of bilateral facial nerve neuropathy from late onset immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor T-cell (CAR-T) therapy for treatment of Multiple Myeloma. <h3>Background:</h3> ICANS is a complication of CAR-T therapy which typically occurs within the first week of treatment. Manifestations can include encephalopathy with confusion and behavioral changes, headache, agraphia, tremors, seizures, cerebral edema, or death. Isolated cranial neuropathies, particularly after this period, have not been reported. <h3>Design/Methods:</h3> Case report. <h3>Results:</h3> Two patients, a 69-year-old male (case 1) and a 67-year-old female (case 2), presented with facial nerve palsy 3 weeks (20 and 21 days respectively) after CAR-T therapy for multiple myeloma. Neither of the patients had developed symptoms of neurotoxicity immediately after CAR-T treatment. Case 1 experienced gradual onset of decreased taste, facial numbness, inability to smile or move his eyebrows, and drooling. Exam showed bilateral facial weakness in a lower motor neuron pattern, worse on the left as compared to the right. Case 2 experienced right-sided facial droop with inability to move her right eyebrow or symmetrically smile, right ear fullness, and right-sided drooling. Exam revealed right-sided facial weakness in a lower motor neuron pattern. MRI of the brain in both patients demonstrated bilateral contrast enhancement of the facial nerves. Cerebrospinal fluid analysis in case 1 showed mildly elevated protein (67 mg/dL), with negative infectious studies, and no evidence of malignancy. Case 2 did not have lumbar puncture, but respiratory viral and bacterial pathogen panel was negative. Both patients were treated with a short course of oral dexamethasone with complete resolution in case 1, and partial improvement of symptoms in case 2. <h3>Conclusions:</h3> Delayed ICANS should be considered in CAR-T patients presenting with isolated cranial neuropathies after ruling out infection and malignancy. Treatment with steroids can lead to recovery. <b>Disclosure:</b> Miss Beck has nothing to disclose. Dr. Hasan has nothing to disclose. Dr. Mehta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Adamas Pharma. Dr. Mehta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbott. Dr. Mehta has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for CNS Ratings. Dr. Valencia Sanchez has nothing to disclose.

Gene Targets of CAR-T Cell Therapy for Glioblastoma.

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood-brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM.

A digital nanoplasmonic microarray immunosensor for multiplexed cytokine monitoring during CAR T-cell therapy from a leukemia tumor microenvironment model

The release of cytokines by chimeric antigen receptor (CAR) T-cells and tumor resident immune cells defines a significant part of CAR T-cell functional activity and patient immune responses during CAR T-cell therapy. However, few studies have so far precisely characterized the cytokine secretion dynamics in the tumor niche during CAR T-cell therapy, which requires multiplexed, and timely biosensing platforms and integration with biomimetic tumor microenvironment. Herein, we implemented a digital nanoplasmonic microarray immunosensor with a microfluidic biomimetic Leukemia-on-a-Chip model to monitor cytokine secretion dynamics during CD19 CAR T-cell therapy against precursor B-cell acute lymphocytic leukemia (B-ALL). The integrated nanoplasmonic biosensors achieved precise multiplexed cytokine measurements with low operating sample volume, short assay time, heightened sensitivity, and negligible sensor crosstalk. Using the digital nanoplasmonic biosensing approach, we measured the concentrations of six cytokines (TNF-α, IFN-γ, MCP-1, GM-CSF, IL-1β, and IL-6) during first 5 days of CAR T-cell treatment in the microfluidic Leukemia-on-a-Chip model. Our results revealed a heterogeneous secretion profile of various cytokines during CAR T-cell therapy and confirmed a correlation between the cytokine secretion profile and the CAR T-cell cytotoxic activity. The capability to monitor immune cell cytokine secretion dynamics in a biomimetic tumor microenvironment could further help in study of cytokine release syndrome during CAR T-cell therapy and in development of more efficient and safer immunotherapies.

Does Cytokine-Release Syndrome Induced by CAR T-Cell Treatment Have an Impact on the Pharmacokinetics of Meropenem and Piperacillin/Tazobactam in Patients with Hematological Malignancies? Findings from an Observational Case-Control Study.

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS.

Safety and efficacy of co-administration of CD19 and CD22 CAR-T cells in children with B-ALL relapse after CD19 CAR-T therapy

BackgroundCD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating relapsed or refractory pediatric B-lineage acute lymphoblastic leukemia (B-ALL). However, poor results are obtained when the same product is reused in patients who relapse after CAR-T. Therefore, there is a need to explore the safety and efficacy of co-administration of CD19- and CD22-targeted CAR-T as a salvage second CAR-T therapy (CART2) in B-ALL patients who relapse after their first CD19 CAR-T treatment (CART1).MethodsIn this study, we recruited five patients who relapsed after CD19-targeted CAR-T. CD19- and CD22-CAR lentivirus-transfected T cells were cultured separately and mixed before infusion in an approximate ratio of 1:1. The total dose range of CD19 and CD22 CAR-T was 4.3 × 106–1.5 × 107/kg. Throughout the trial, we evaluated the patients’ clinical responses, side effects, and the expansion and persistence of CAR-T cells.ResultsAfter CART2, all five patients had minimal residual disease (MRD)-negative complete remission (CR). The 6- and 12-month overall survival (OS) rates were 100%. The median follow-up time was 26.3 months. Three of the five patients bridged to consolidated allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CART2 and remained in MRD-negative CR at the cut-off time. In patient No. 3 (pt03), CAR-T cells were still detected in the peripheral blood (PB) at 347 days post-CART2. Cytokine release syndrome (CRS) only occurred with a grade of ≤ 2, and no patients experienced symptoms of neurologic toxicity during CART2.ConclusionsMixed infusion of CD19- and CD22-targeted CAR-T cells is a safe and effective regimen for children with B-ALL who relapse after prior CD19-targeted CAR-T therapy. Salvage CART2 provides an opportunity for bridging to transplantation and long-term survival.Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032211. Retrospectively registered: April 23, 2020.

CAR T-Cell Persistence Correlates with Improved Outcome in Patients with B-Cell Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has led to profound and durable tumor responses in a relevant subset of patients with relapsed/refractory (r/r) B-cell lymphomas. Still, some patients show insufficient benefit or relapse after CAR T-cell therapy. We performed a retrospective study to investigate the correlation between CAR T-cell persistence in the peripheral blood (PB) at 6 months, assessed by droplet digital PCR (ddPCR), with CAR T-cell treatment outcome. 92 patients with r/r B-cell lymphomas were treated with CD19-targeting CAR T-cell therapies at our institution between 01/2019-08/2022. Six months post-treatment, 15 (16%) patients had no detectable circulating CAR-T constructs by ddPCR. Patients with CAR T-cell persistence had a significantly higher CAR T-cell peak (5432 vs. 620 copies/ug cfDNA, p = 0.0096), as well as higher incidence of immune effector cell-associated neurotoxicity syndrome (37% vs. 7%, p = 0.0182). After a median follow-up of 8.5 months, 31 (34%) patients relapsed. Lymphoma relapses were less frequent among patients with CAR T-cell persistence (29% vs. 60%, p = 0.0336), and CAR T-cell persistence in the PB at 6 months was associated with longer progression-free survival (PFS) (HR 2.79, 95% CI: 1.09-7.11, p = 0.0319). Moreover, we observed a trend towards improved overall survival (OS) (HR 1.99, 95% CI: 0.68-5.82, p = 0.2092) for these patients. In our cohort of 92 B-cell lymphomas, CAR T-cell persistence at 6 months was associated with lower relapse rates and longer PFS. Moreover, our data confirm that 4-1BB-CAR T-cells have a longer persistence as compared to CD-28-based CAR T-cells.

How I treat refractory/relapsed diffuse large B‐cell lymphomas with CD19‐directed chimeric antigen receptor T cells

Chimeric antigen receptor (CAR) T cells targeting CD19 represent a promising salvage immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), offering ~40% of long-term responses. In everyday clinical practice, haematologists involved in CAR T cell treatment of patients with R/R DLBCL have to deal with diagnostically complex cases and difficult therapeutic choices. The availability of novel immunotherapeutic agents for R/R DLBCL and recent advances in understanding CAR T-cell failure mechanisms demand a rational approach to identify the best choice for bridging therapy and managing post-CAR T-cell therapy relapses. Moreover, positron emission tomography/computerised tomography may result in false-positive interpretation, highlighting the importance of post-treatment biopsy. In this review, we discuss all above issues, presenting four instructive cases, with the aim to provide criteria and new perspectives for CAR T-cell treatment of DLBCL.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma.

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice.

Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19+ cells. Increased myeloid subsets, including CD11c+ DCs and F4/80+ macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase.

Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies.

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p= 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.

Outcome Prediction in Patients With Large B-cell Lymphoma Undergoing Chimeric Antigen Receptor T-cell Therapy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy has led to a fundamental shift in the management of relapsed and refractory large B-cell lymphoma. However, our understanding of risk factors associated with non-response is still insufficient and the search for predictive biomarkers continues. Some parameters measurable on 18F-fluorodeoxyglucose positron emission tomography (PET) may be of additional value in this context. A total of 47 individuals from three German university centers who underwent re-staging with PET prior to CAR T-cell therapy were enrolled into the present study. After multivariable analysis considering tumor characteristics and patient factors that might affect progression-free survival (PFS), we investigated whether metabolic tumor volume (MTV) or maximum standardized uptake value (SUVmax) further improve risk stratification. Their most suitable cut-offs were determined by Cox and logistic regression. Forward selection identified extra-nodal disease as the most predictive factor of those routinely available, and we found it to be associated with significantly inferior overall survival after CAR T-cell treatment (P = 0.012). Furthermore, patients with MTV and SUVmax higher than the optimal threshold of 11 mL and 16.7, respectively, experienced shorter PFS (P = 0.016 and 0.002, respectively). Hence, these risk factors might be useful for selection of individuals likely to benefit from CAR T-cell therapy and their management.

Protection of gemcitabine-loaded polylactic-co-glycolic acid microspheres combined with CAR-T treatment against pancreatic ductal adenocarcinoma

Pancreas ductal adenocarcinoma has a highly aggressive phenotype and is one of the most lethal malignancies in the world. Although the use of FOLFIRINOX and abraxane plus gemcitabine chemotherapy regimens have improved patient care, their recurrence rates and long-term survival are still not promising. In this study, PLGA/gemcitabine microspheres were prepared by emulsification–solvent volatilization using gemcitabine as the drug model, and scanning electron microsopy showed that the microspheres had a smooth surface, small size, and large specific surface area. The PLGA microspheres have a high loading capacity and are capable of long-term release. The combination of PLGA/gemcitabine microspheres with chimeric antigen receptor T-cell treatment can regulate MUC1 expression in epithelial cells and reduce the aggressiveness of tumors; thus, it is expected to be applied in the treatment of pancreatic ductal adenocarcinoma.

Chimeric Antigen Receptor (CAR) T-cell Treatment in Renal Cell Carcinoma: Current Clinical Trials and Future Directions

Renal cell carcinoma (RCC) has long been found to be responsive to immunotherapy. While high dose interleukin-2 resulted in some durable remissions, this treatment has largely been replaced by immune checkpoint inhibitor therapy, due to the safer toxicity profile and emerging evidence for long term remissions. However, the majority of patients continue to face disease progression and death from metastatic RCC. Chimeric antigen receptor T-cells (CAR T) represent the next step in immunotherapy for this malignancy and hold promise for a higher rate of durable remissions. The realization of this therapeutic strategy for RCC will require identification of the best tumor antigen and T cell modifications and will depend on achieving remissions with an acceptable toxicity profile. This review summarizes current CAR T-cell treatment targets and clinical trials for metastatic RCC, highlighting the potential therapeutic impact as well as obstacles to successful development.

Rapid Response to Idecabtagene Vicleucel in a Myeloma Patient Refractory to Multiple Prior Lines of Anti-BCMA Directed Therapies

Targeting B-cell maturation antigen (BCMA) with antibody drug conjugates (ADCs), bispecific antibodies, or chimeric antigen receptor (CAR) T-cells is an established strategy in relapsed/refractory multiple myeloma (RRMM). In most European countries, the respective agents are approved after exposure to at least three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody. It still needs to be clarified whether sequential treatment with different anti-BCMA directed agents is safe and effective. In some countries, payers do not cover/reimburse CAR T-cell treatment directed against BCMA if the patient was previously exposed to an anti-BCMA ADC or bispecific antibody. To the best of our knowledge, we describe the first case of rapid response to BCMA-directed CAR-T cells (idecabtagene vicleucel; Ide-cel) in a heavily pretreated patient who had already failed two prior lines of anti-BCMA directed therapies. A 54-year-old female with IgG kappa MM harboring chromosomal deletion 17p and gain of 1q21 presented to our department. Initial treatment consisted of PI/IMiD-based induction therapy, high-dose melphalan as part of tandem autologous stem cell transplantations followed by lenalidomide maintenance. Very good partial remission (VGPR) lasted 3 years, and the patient became triple-class (PI, IMiD, anti-CD38)-refractory only two years after first relapse. We enrolled the patient in a phase I/II trial of the anti-BCMA bispecific antibody teclistamab. Cytokine release syndrome (CRS) grade III complicated teclistamab treatment and the patient showed biochemical relapse and progressive osteolytic lesions after being 4 months on study. After failing two subsequent alkylator-based lines of therapy including melphalan flufenamid, the patient was treated with belantamab mafodotin and progressed after two months. Treatment was switched to isatuximab/pomalidomide/dexamethasone. The latter combination represented the 11th line of therapy for this patient. After approval of Ide-cel in Germany in 2021, leukapheresis for successive CAR T-cell production was performed. Since the patient showed a partial response after 1 month, this bridging therapy with isatuximab/pomalidomide/dexamethasone was continued until successful CAR manufacturing. Unfortunately, the patient experienced disease progression prior to lymphodepletion therapy with progressive transfusion-dependent pancytopenia and subtotal infiltration of bone marrow by malignant plasma cells. PET/CT showed no evidence of extramedullary disease. Lymphodepletion with fludarabine/cyclophosphamide according to the phase-II KarMMa protocol was initiated, and 441.5 x 10exp6 CAR T-cells were infused. The inpatient stay was complicated by grade I CRS and septicemia due to gram-negative bacteria requiring vasopressor treatment for 48 hours. Two weeks after infusion of Ide-cel, significant increases of serum uric acid and lactate dehydrogenase levels indicative of tumor lysis syndrome were detected, requiring application of rasburicase and intravenous hydration. After stabilization of serum creatinine values, serological assessment of disease activity three weeks after CAR T-cell infusion already showed decrease of serum kappa free light chains from 3328 mg/l at admission to 4 mg/l and an unprecedented depth of remission (VGPR, see Figure 1). Currently, the patient's state of remission is still improving. Updated follow-up and data on CAR T-cell expansion and persistence will be presented at the meeting. Our case illustrates rapid response to anti-BCMA CAR-T cells (Ide-cel) after failing treatment with an ADC and a bispecific antibody directed against BCMA. This demonstrates that sequential treatment can be effective even after multiple prior lines of anti-BCMA directed therapies. Patients with prior exposure to anti-BCMA agents should have access to anti-BCMA CAR T-cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results of Fumanba-1: A Phase 1b/2 Study of a Novel Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT103A) in Patients with Relapsed and/or Refractory Multiple Myeloma

Background： CT103A, is a fully human BCMA-specific chimeric antigen receptor (CAR) T-cell therapy product. Our previous results demonstrated that CT103A leads to early, deep and durable responses and a favorable safety profile in heavily pretreated relapsed and refractory multiple myeloma (RRMM) subjects. Besides, initial results showed that these subjects also experienced low host anti-CAR immunogenicity, which was probably due to the unique fully human single-chain variable fragments (scFvs). Here, we report updated data on more subjects from the FUMANBA-1 study with a longer duration of follow-up. Methods： FUMANBA-1 (NCT05066646) is a phase 1b/2 study of CT103A that is conducted in 14 centers in China. This study enrolled RRMM subjects who received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. Subjects who have progressed on previous BCMA-CAR T-cell therapy were also included. Fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) were used for 3 consecutive days as the lymphodepletion regimen. All subjects received a single infusion of CT103A at the dose of 1.0 x 106 CAR+ T cells/Kg. The objective of this study is to evaluate the efficacy, safety and pharmacokinetics. CRS and ICANS were graded according to ASTCT criteria, and other adverse events (AEs) were graded by CTCAE v5.0. The response was evaluated conforming to the IMWG 2016 consensus criteria. MRD negativity was evaluated in bone marrow aspirate by standardized Euroflow flow cytometry with a minimum sensitivity of 10-5 nucleated cells. Immunogenicity was assessed by MSD-based antidrug antibody (ADA) assay. Results: As of the July 22, 2022, 103 subjects [53.4% male; median age 58.0 years (range 39-70)] with RRMM received CT103A (17 in phase 1b; 86 in phase 2) with a median follow-up time of 12.2 months (range 0.2 to 25.6). The treated subjects had received a median of 4 (range 3-23) lines of prior therapy. 27.2% and 18.4% of subjects were previously treated with auto-HSCT and anti-CD38 antibody respectively. Notably, 11.7% had previously received CAR T-cell therapy. Moreover, 9.7% of the subjects had extramedullary plasmacytoma at baseline, and 48.5% had high-risk cytogenetics. 100 subjects were evaluable for efficacy assessment. The median time to first response was 16 days (range 11-123). A 95% ORR was observed, with 74% ≥ CR, 17% VGPR, and 4% PR. Among them, 91 subjects who have completed 3-month follow-up achieved 96.7% ORR, with 76.9% ≥ CR, 15.4% VGPR, and 4.4% PR. Median DOR and median PFS have not reached. For 12 subjects who have previously been treated with CAR T-cell therapy, ORR was 75%, with ≥CR rate of 41.7%, VGPR of 8.3%, and PR of 25%. Notably, among the subjects who achieved sCR, 4/5 (80%) still sustained sCR over one year post infusion. Of the 100 subjects with evaluable samples, 95% achieved MRD-negativity with a median time to MRD-negative of 15 days (range 14-186), and all subjects with CR/sCR were MRD-negative. Furthermore, 80.0% (95%CI 67.6-88.6%) achieved sustained MRD negativity over 12 months. The most common ≥ grade 3 treatment-related AE was expected hematological toxicity. 93.2% of the subjects experienced CRS, which was mostly ≤grade 2. There was only one≥ grade 3 CRS which was grade 4. All CRS cases were manageable using conventional CRS intervention, including tocilizumab and steroids. The median time to CRS onset was six days (range 1-13) with a median duration of 5 days (range 2-30). Only 2 (1.9%) subjects experienced ICANS, which were ≤grade 2 and manifested as a transiently decreased level of consciousness and soon recovered without intervention. The expansion of CT103A reached the median peak level of 86376.5 copies/μg gDNA at a median of 12 days. CT103A was still detectable in 51.1% (23/45) subjects at 12 months and 45.5% (10/22) subjects at 15 months after infusion. In addition, only 13 of 98 subjects (13.3%) with evaluable samples were detected to be positive for the anti-drug antibody. By months 3 and 6 after infusion, 2/78 (2.6%) and 5/61 (8.2%) of the subjects were ADA-positive. Conclusion: The updated data from FUMANBA-1 demonstrated the sustained clinical benefit of CT103A, especially for those who previously received CAR T-cell treatment. The depth and durability of responses achieved with CT103A were consistent with their robust and prolonged persistence.

Murine allogeneic CAR T cells integrated before or early after posttransplant cyclophosphamide exert antitumor effects

AbstractRelapse limits the therapeutic efficacy both of chimeric antigen receptor (CAR) T cells and allogeneic hematopoietic cell transplantation (allo-HCT). Patients may undergo these therapies sequentially to prevent or treat relapsed malignancy. However, direct integration of the 2 therapies has been avoided over concerns for potential induction of graft-versus-host disease (GVHD) by allogeneic CAR T cells. We have shown in murine T-cell-replete MHC-haploidentical allo-HCT that suppressive mechanisms induced immediately after posttransplant cyclophosphamide (PTCy), given on days +3/+4, prevent GVHD induction by alloreactive T cells infused as early as day +5. Therefore, we hypothesized that allogeneic CAR T cells given in a similarly integrated manner in our murine MHC-haploidentical allo-HCT model may safely exert antitumor effects. Indeed, allogeneic anti-CD19 CAR T cells given early after (day +5) PTCy or even prior to (day 0) PTCy cleared leukemia without exacerbating the cytokine release syndrome occurring from the MHC-haploidentical allo-HCT or interfering with PTCy-mediated GVHD prevention. Meanwhile, CAR T-cell treatment on day +9 or day +14 was safe but less effective, suggesting a limited therapeutic window. CAR T cells infused before PTCy were not eliminated, but surviving CAR T cells continued to proliferate highly and expand despite PTCy. In comparison with infusion on day +5, CAR T-cell infusion on day 0 demonstrated superior clinical efficacy associated with earlier CAR T-cell expansion, higher phenotypic CAR T-cell activation, less CD4+CD25+Foxp3+ CAR T-cell recovery, and transcriptional changes suggesting increased activation of CD4+ CAR T cells and more cytotoxic CD8+ CAR T cells. This study provides mechanistic insight into PTCy’s impact on graft-versus-tumor immunity and describes novel approaches to integrate CAR T cells and allo-HCT that may compensate for deficiencies of each individual approach.

Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis

AbstractAnti-CD19 chimeric antigen receptor (CAR) T-cells represent a major advance in the treatment of relapsed/refractory aggressive B-cell lymphomas. However, a significant number of patients experience failure. Among 550 patients registered in the French registry DESCAR-T, 238 (43.3%) experienced progression/relapse, with a median follow-up of 7.9 months. At registration, 57.0% of patients presented an age-adjusted International Prognostic Index of 2 to 3, 18.9% had Eastern Cooperative Oncology Group performance status ≥2, 57.1% received >3 lines of treatment prior to receiving CAR T-cells, and 87.8% received bridging therapy. At infusion, 66% of patients presented progressive disease, and 38.9% had high lactate dehydrogenase (LDH). Failure after CAR T-cell treatment occurred after a median of 2.7 months (range: 0.2-21.5). Fifty-four patients (22.7%) presented very early failure (day [D] 0-D30); 102 (42.9%) had early failure (D31-D90), and 82 (34.5%) had late (>D90) failure. After failure, 154 patients (64%) received salvage treatment: 38.3% received lenalidomide, 7.1% bispecific antibodies, 21.4% targeted treatment, 11% radiotherapy, and 20% immunochemotherapy with various regimens. Median progression-free survival was 2.8 months, and median overall survival (OS) was 5.2 months. Median OS for patients failing during D0-D30 vs after D30 was 1.7 vs 3.0 months, respectively (P = .0001). Overall, 47.9% of patients were alive at 6 months, but only 18.9% were alive after very early failure. In multivariate analysis, predictors of OS were high LDH at infusion, time to CAR-T failure <D30, and high C-reactive protein at infusion. This multicentric analysis confirms the poor outcome of patients relapsing after CAR T-cell treatment, highlighting the need for further strategies dedicated to this population.

Lymphoma tumor burden before chimeric antigen receptor T-Cell treatment: RECIL vs. Lugano vs. metabolic tumor assessment.

PurposeHigh tumor burden has emerged as a negative predictor of efficacy in chimeric antigen receptor T-cell therapy (CART) in patients with refractory or relapsed large B-cell lymphoma. This study analyzed the deviation among imaging-based tumor burden (TB) metrics and their association with progression-free (PFS) and overall survival (OS).Materials and methodsIn this single-center observational study, we included all consecutively treated patients receiving CD19 CART with available baseline PET-CT imaging. Imaging-based TB was determined based on response evaluation criteria in lymphoma (RECIL), the Lugano criteria, and metabolic tumor volume. Total, nodal and extranodal TB were represented, according to the respective criteria, by sum of longest diameters (TBRECIL), sum of product of perpendicular diameters (TBLugano), and metabolic tumor volume (TBMTV). Correlation statistics were used for comparison. Proportional Cox regression analysis studied the association of TB metrics with PFS and OS.Results34 consecutive patients were included (median age: 67 years, 41% female) with total median baseline TBRECIL of 12.5 cm, TBLugano of 4,030 mm2 and TBMTV of 330 mL. The correlation of TBRECIL and TBLugano with TBMTV was strong (ρ=0.744, p<0.001 and ρ=0.741, p<0.001), with lowest correlation for extranodal TBRECIL with TBMTV (ρ=0.660, p<0.001). Stratification of PFS was strongest by total TBMTV>50% (HR=2.915, p=0.042), whereas total TBRECIL>50% and total TBLugano>50% were not significant (both p>0.05). None of the total TB metrics were associated with OS (all p>0.05).ConclusionPre-CART TB metrics vary significantly based on the assessment method, impacting their association with survival outcomes. The correlation between TBRECIL, TBLugano and TBMTV was influenced by disease phenotype and prior bridging therapy. TB method of assessment must be considered when interpreting the impact of TB on outcomes in clinical trials. Considering the heterogeneity, our results argue for standardization and harmonization across centers.

CAR-T Immunotherapy to Beat Solid Tumors: From Challenges to Improvements

Chimeric antigen receptor T (CAR-T) cell immunotherapy shows potential and guarantee for clinical application in solid tumor treatment, although a section of difficulties must be overcome. Compared with conventional antitumor therapies, the advantages of CAR-T cell treatment include high specificity, great killing power, and long-term effectiveness. But various difficulties in treating solid tumors by CAR-T immunotherapy include intracellular signaling of CARs, immune escape due to antigenic heterogeneity of malignant tumors, physical or cytokine barriers that prevent CAR-T cell entry or limit their persistence, tumor microenvironment of other immunosuppressive molecules, and side effects. This paper describes CAR-T immunotherapy's mechanisms, development, and applications and discusses the status, difficulties, solutions, and future directions of treating solid tumors by CAR-T immunotherapy.