Neurotoxicity Research Articles

Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients

AbstractHuman herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell–associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity

AbstractAxicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

B-cell maturation antigen-based therapies post-talquetamab in relapsed or refractory multiple myeloma.

Talquetamab recently received approval for relapsed refractory multiple myeloma. However, there is currently no available data on how patients perform with BCMA based agents after progression on talquetamab. Herein, we present the outcome of 10 patients who received BCMA based therapies following talquetamab. The median follow-up was 9.5 months (range: 6-24 months). The median progression free survival was 5.5 months (range: 1-10 months). Patients had varying grades of cytokine release syndrome and Immune effector cell-associated neurotoxicity syndrome. Our results suggest that treatment with talquetamab followed by BCMA based therapies is feasible and can be considered as clinically indicated.

Potentially fatal complications of new systemic anticancer therapies: pearls and pitfalls in their initial management.

Various types of immunotherapy (i.e. immune checkpoint inhibitors [ICIs], chimeric antigen receptor [CAR] T-cells and bispecific T-cell engagers [BiTEs]) and antibody drug conjugates (ADCs) have been used increasingly to treat solid cancers, lymphomas and leukaemias. Patients with serious complications of these therapies can be presented to physicians of different specialties. In this narrative review we discuss potentially fatal complications of new systemic anticancer therapies and some practical considerations for their diagnosis and initial treatment. Clinical presentation of toxicities of new anticancer therapies may be unpredictable and nonspecific. They can mimic other more common medical conditions such as infection or stroke. If not recognized and properly treated these toxicities can progress rapidly into life-threatening conditions. ICIs can cause immune-related inflammatory disorders of various organ systems (e.g. pneumonitis or colitis), and a cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may develop after treatment with CAR T-cells or BiTEs. The cornerstones of management of these hyper-inflammatory disorders are supportive care and systemic immunosuppressive therapy. The latter should start as soon as symptoms are mild-moderate. Similarly, some severe toxicities of ADCs also require immunosuppressive therapy. A multidisciplinary team including an oncologist/haematologist and a corresponding organ-site specialist (e.g. gastroenterologist in the case of colitis) should be involved in the diagnosis and treatment of these toxicities. Health professionals should be aware of potential serious complications of new systemic anticancer therapies. Early diagnosis and treatment with adequate supportive care and immunosuppressive therapy are crucial for the optimal outcome of patients with these complications.

Immunotherapy of Hematological Malignancies of Human B-Cell Origin with CD19 CAR T Lymphocytes.

Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Maraleucel), has provided hope for those with r/r NHL and ALL. These new cell-based immunotherapies use genetically engineered chimeric antigen receptor (CAR) T-cells, whose success can be attributed to CAR's high specificity in recognizing B-cell-specific CD19 surface markers present on various B-cell malignancies and the subsequent initiation of anti-tumor activity. The efficacy of these treatments has led to promising results in many clinical trials, but relapses and adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity (NT) remain pervasive, leaving areas for improvement in current and subsequent trials. In this review, we highlight the current information on traditional treatments of NHL and ALL, the design and manufacturing of various generations of CAR T-cells, the FDA approval of Kymriah, Yescarta Tecartus, and Breyanzi, and a summary of prominent clinical trials and the notable disadvantages of treatments. We further discuss approaches to potentially enhance CAR T-cell therapy for these malignancies, such as the inclusion of a suicide gene and use of FDA-approved drugs.

Clinical and Neuroradiological Features of Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma (MCL) (S23.007)

Clinical and Neuroradiological Features of Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma (MCL) (S23.007)

Danger in plain sight: determining who is at highest risk for cefepime induced neurotoxicity and its associated morbidity and mortality.

Cefepime is a fourth-generation cephalosporin that is widely used to treat sepsis but is associated with a potentially dangerous neurotoxicity syndrome, cefepime-induced neurotoxicity (CIN). As a result, patients treated with cefepime may be at higher risk for morbidity, including seizures, and mortality. Though the recent ACORN trial concluded that cefepime does not increase the risk of mortality, most of these patients were not critically ill or elderly, two of the most at risk populations for CIN. Further, diagnosis may be difficult in the critical care setting as patients may have multiple reasons for encephalopathy. Therefore, this population in particular should be studied and monitored closely for CIN. Importantly, there are not well defined diagnostic criteria for CIN to guide evaluation and management. Defining the risk factors for CIN and using laboratory and EEG to help support the clinical diagnosis could be helpful in early recognition of CIN to help institute treatment and to rule out seizures. In this mini review, we highlight risk factors for CIN, discuss the possible value of EEG, and propose a diagnostic and management approach in the evaluation and management of CIN.

Abstract CT071: Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy

Abstract Introduction: Despite therapeutic advances, multiple myeloma remains incurable. BCMA targeting immunotherapies, such as bispecific T-cell engagers (TCE) and autologous CAR-T provide high response rates, but relapses are common. Autologous CAR-T are logistically challenging due to the need for apheresis, prolonged manufacturing and occasional manufacturing failures. Importantly, pts who have progressed after a prior BCMA targeting immunotherapy are an emerging area of high unmet need. Emerging data indicate that autologous CAR-T have lower clinical activity in pts ho have progressed on TCE. Methods: P-BCMA-ALLO1 is an allogeneic CAR-T therapy manufactured from healthy donor T-cells available “off-the-shelf” and being evaluated in a phase 1 clinical trial (P-BCMA-ALLO1-001) in RRMM pts. This primary objective is to determine the maximum tolerated dose of P-BCMA-ALLO1, and the key secondary objective is to investigate the anti-myeloma activity. The pts must have progressed on a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody. The study allows enrollment of pts who have received prior BCMA targeting therapy. The study is exploring escalating P-BCMA-ALLO1 doses and several different lymphodepletion chemotherapy (LD) regimens. Here we report the safety and early efficacy results for the 5 pts who were treated with P-BCMA-ALLO1 after having progressed on BCMA targeting CAR-T, TCE or both. These pts were treated in arms P1 (LD: cyclophosphamide (cy) 500 mg/m2 + fludarabine (flu) 30 mg/m2 X 3 days) or arm P2 (LD: cy 1000 mg/m2 + flu 30 mg/m2 X 3 days) at a P-BCMA-ALLO1 dose of > 2 X 106 to <6 X 106 cells/kg. Results: The median pt age was 62 years and median prior lines of therapy was 10. Three pts were treated in arm P2 and 2 in arm P1. Two pts had received prior teclistamab, 2 had received prior CAR-T and 1 had received prior teclistamab and CAR-T. P-BCMA-ALLO1 was well tolerated with no dose limiting toxicities or graft vs. host disease. Three of the five pts developed cytokine release syndrome (all grade (G) 2) and one developed G2 immune effector cell neurotoxicity syndrome. Three of the five pts (60%) achieved clinical responses with all three achieving the best response of very good partial response. The two non-responders had previously received and failed to achieve clinical response with teclistamab. One pt who had previously received both teclistamab and CAR-T achieved VGPR. Conclusion: In conclusion, P-BCMA-ALLO1 is an allogeneic CAR-T that is available “on-demand” with activity in RRMM pts who have progressed following prior BCMA targeted CAR-T and TCE. We believe this is the first such report of an allogeneic CAR-T showing clinical activity in such a pt population with high unmet need. Enrollment is continuing and updated data will be presented at the meeting. Citation Format: Bhagirathbhai Dholaria, Leyla Shune, Andrew Kin, Katherine McArthur, Jeff D. Eskew, Christopher E. Martin, Sabrina Haag, Joanne McCaigue, Hamid Namini, Sam DePrimo, Stacey Cranert, Julia Coronella, Devon Shedlock, Rajesh Belani. Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT071.

Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immuneeffector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

Abstract CT244: HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II)

Abstract Background: HR001 is a CD19-targeted CAR-T cell for patients with relapsed and refractory non-Hodgkin's (R/R NHL). Here, we report the primary results of the phase 2 study (HRAIN01-NHL01-II). Methods: HRAIN01-NHL01-II is an open-label, single-arm, and multicenter (17 centers) study in China. It enrolled R/R NHL patients treated with at least two lines of therapy (must-have anthracycline and CD20-targeted agents) or after autologous hematopoietic stem cell transplantation. All patients received a single infusion of HR001 at the 2.0 × 106 CAR+T cells/kg dose. The disease response was evaluated by the independent review committee with Lugano response criteria [2014]. Results: As of May 16th, 2023, 81 R/R NHL patients with ECOG 0-1 at baseline received the infusion HR001 from the Jinshan manufacturing facility [51.9% male; median age 53.4 years (range 23~74); 3.7% CD19 negative; 91.4% diffuse large B-cell lymphoma; 79.0% III-IV of Ann Arbor classification or Lugano] with a median follow-up of 160 days (range 7 to 454). The median time to best response was 30 days (range 28-358). The 3-month, 6 month and best objective response rate (ORR) was 53.1%(95% CI: 41.7-64.3), 45.7%(95% CI: 34.6-57.1) and 74.1% (95% CI: 63.1-83.2) respectively. The 3-month, 6 month and best complete response rate (CRR) was 32.1%(95% CI: 22.2-43.4), 29.6%(95% CI: 20.0-40.8) and 49.4%(95% CI: 38.1-60.7) respectively. Median duration of response (DOR) and progression-free survival (PFS) were 339 days (95% CI: 149-NE) and 176 days (95% CI: 91-NE) respectively. The overall survival (OS) was not reached. The most common treatment-related adverse events (AEs) happened in the hematologic system. The cytokine release syndrome (CRS) occurred in 95.1% of patients, with ≥3 grade CRS observed in 3.7% of patients. Immune effector cell-associated neurotoxicity syndrome (ICANS) happened in 8.6% of patients, without any ≥ 3 grade ICANS reported. The treatment-related mortality was 1.2%. The median time to CAR T-cell peak expansion was 240 hours (120~672) after infusion, median maximum expansion (Cmax) was 17413.9 copies/μg DNA (124.9~136382.2), and median AUC0-28d was 3201014.0 copies/μg DNA (205082.8~18400016.2). Positive tests for the anti-drug antibody (ADA) were noted in 14.8% of patients, while neutralizing antibody (Nab) tests were positive in 3.7% of patients. Among Nab-positive patients, the complete response was maintained until follow-up. Conclusions: Patients with R/R NHL could benefit from the HR001 treatment with satisfactory objective response, durable remission, and favorable safety profile. Citation Format: Yian Zhang, Yuhua Li, Kai Hu, Wuping Li, Hongwei Xue, Qi Deng, Zheng Ge, Liangquan Geng, Xianmin Song, Kang Yu, Hongmei Jing, Bing Chen, Xin Li, Zhimin Zhai, Jianping Shen, Jiang Cao, Qingming Wang, Peng Liu. HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT244.

Abstract CT143: IFN-γ and donor leukocyte infusion to treat relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation

Abstract Introduction: Allogeneic stem cell transplantation (alloSCT) can provide a cure for myeloid malignancies partially through the graft-vs-leukemia effect (GVL), wherein donor-derived alloreactive T cells attack recipient leukemia cells. Preclinical data strongly suggested IFN-γ is crucial for effective GVL against myeloblastic leukemia. IFN-γ receptor gene-deficient myeloblastic leukemia were resistant to GVL in mouse models (Matte-Martone, Shlomchik JCI 2017). IFN-γ upregulated HLA expression in relapsed myeloblasts in vitro (Christopher NEJM 2018, Toffalori Nat Med 2019). We hypothesized that IFN-γ would sensitize myeloblasts to alloreactive T cells and promote GVL. Here, we present the results of a phase 1 study to evaluate the safety of IFN-γ combined with donor leukocyte infusions (DLI) for relapsed myeloblastic malignancies post-transplant (NCT04628338). Methods: HLA-matched donor alloSCT recipients with relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and no active graft-versus-host disease (GVHD) were eligible. Patients self-administered 100mcg IFN-γ (Actimmune, Horizon Therapeutics) three times a week for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Flow cytometry-based surface HLA expression and single-cell RNAseq (scRNAseq) were analyzed using bone marrow (BM) collected before and after IFN-γ. Results: Seven patients with high-risk diseases (2 MDS and 5 AML) were enrolled. There were no serious adverse events during IFN-γ monotherapy. After DLI, 5 patients developed grade I-II GVHD along with immune effector cell-associated neurotoxicity syndrome (grade 1 or 2; n=2) and idiopathic pneumonia syndrome (IPS; n=1). All immune-mediated toxicities, including IPS, resolved with corticosteroids. 4 out of 6 DLI recipients achieved minimal residual disease negative complete remissions and full donor hematopoietic cell reconstitution. The median overall survival was 579 days (range, 97-906) in responders. Myeloid blasts upregulated HLA-DR after IFN-γ, and enrichment of recipient malignant hematopoietic stem cells expressing CIITA was observed in post-IFN-γ BM by scRNAseq. Conclusions: This first in human use of IFN-γ to treat post-transplant relapse was safe, with a promising efficacy signal when combined with DLI. Correlative studies support our hypothesis that in vivo IFN-γ activates myeloblasts, manifest by HLA-DR upregulation and CIITA induction. We plan to design a phase 2 trial to formally test the efficacy of this novel immunotherapeutic approach to boost GVL in alloSCT. Citation Format: Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Scott N. Furlan, Warren D. Shromchik. IFN-γ and donor leukocyte infusion to treat relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT143.

Abstract CT129: A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer

Abstract Background: GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, is designed to overcome the limitations of conventional CAR T-cells in solid tumor malignancies by pairing solid tumor CAR T-cells with CD19-targeting CAR T-cells to amplify the proliferation and activation of the solid tumor CAR T component. GCC19CART targets guanylate cyclase-C (GCC), which is reported to be expressed in the metastatic lesions of 70%-80% of subjects with colorectal cancers and largely restricted to the intestinal tract. A Phase 1 investigator-initiated clinical trial conducted in China showed preliminary efficacy with an overall response rate (ORR) at dose level 1 (1x106 CAR T-cells/kg) of 15.4% ORR (2/13) and 50% ORR (4/8) in dose level 2 (2x106 CAR T-cells/kg). Common side effects included cytokine release syndrome (CRS) and diarrhea/colitis. Immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in a smaller proportion of patients. A phase 1 study was initiated in the United States in August 2022 for patients with metastatic colorectal cancer refractory to standard of care chemotherapy. As of a data cutoff on ​November 1, 2023, 4 subjects have been treated in the initial dose level. Methods: Subjects were initially screened for GCC expression; this requirement was later discontinued when immunohistochemistry studies revealed that the frequency of positive GCC expression exceeded 95%. Eligible subjects underwent leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART. Responses were assessed by RECIST v1.1 by site investigator review and an independent third-party imaging contract research organization. Results: 4 subjects have been dosed at level 1 (1x106 cells/kg) and completed the DLT period at the time of data cutoff. The most common adverse events were CRS in 4/4 subjects (Grade 1: 2/4 (50%) or Grade 2: 2/4 (50%)) and diarrhea in 3/4 subjects (Grade 1: 1/4 (25%), Grade 2: 1/4 (25%), or Grade 3: 1/4 (25%)). Three out of four patients had a mild tremor (Grade 1) that resolved with corticosteroids and no other evidence of neurotoxicity. The combined overall response rate (ORR) was 50% (2/4) by independent review. Two subjects demonstrated a partial response (PR) while 1 additional subject had partial metabolic response (PMR) on PET/CT with stable disease (SD) and 1 patient had progressive disease per RECIST 1.1. Per site investigator review, the ORR was 25%, with 1 confirmed PR and 3 SD assessed as best response. The median PFS was 3.8 months in the dose level 1 group. Conclusions: Preliminary results demonstrate that GCC19CART has meaningful clinical activity and an acceptable safety profile in refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented, including from patients treated at dose level 2 (2x106 CAR T-cells/kg). Clinical trial information: NCT05319314. Citation Format: Bridget P. Keenan, Christopher H. Lieu, Marwan Fakih, Dongqi Chen, Lucy Lu, Eric Rowinsky, Victor Lu, Lei Xiao, Alan P. Venook, Benjamin Schlechter. A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT129.

Abstract CT096: Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers

Abstract Purpose: First-in-human Phase I study for advanced MUC1* positive breast cancer with autologous T cells engineered to express either a chimeric antigen receptor, huMNC2-CAR44 or huMNC2-CAR22, which specifically bind to a cleaved form of MUC1 (MUC1*); evaluate the safety and preliminary anti-tumor activity. Methods: MUC1* (muk 1 star) is the growth factor receptor form of MUC1, created by cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes that are correlated with poor prognosis. huMNC2 does not bind to full-length MUC1, which is expressed on all normal epithelial cells. huMNC2-scFv was incorporated into huMNC2-CAR44, comprising a CD8 hinge and transmembrane region, 4-1BB costimulatory domain and wild-type CD3z. huMNC2-scFv was also incorporated into huMNC2-CAR22 wherein the hinge, transmembrane and co-stimulatory portions were derived from CD28 and CD3z bears the 1XX mutations to increase in vivo persistence. Inclusion criteria require that the patient’s tumor is at least 30% MUC1* positive and that patient has progressed through 2 or 3 prior therapies, while in the metastatic setting. Patients receive standard Cy/Flu lymphodepletion approximately 3-days before CAR T treatment, administered at 1 of 4 dose levels ranging from 3.3X10^5 up to 1.0X10^7 CAR+ T cells. Results: To date, 8 patients have been treated with huMNC2-CAR44. No patients experienced neuro toxicities. No off-target toxicities were observed. 3 patients experienced CRS Grade 1-3. In 6 of the 8 patients, side effects were non-existent or minimal. However, one patient experienced a Grade 5 SAE that was deemed to be possibly related to the treatment. Best responses include Partial Responses and Stable Disease at a low CAR-T dose. Greatest efficacy was observed for patients whose biopsy showed H Scores >120. Patients are currently being enrolled for treatment with huMNC2-CAR22, where the 1XX mutations are expected to increase in vivo persistence, durability of response and reduced incidence of CRS. Conclusions: These data support a conclusion that the MUC1* antibody, huMNC2, is safe and could have high therapeutic value as a CAR T treatment for solid tumors with moderate to high antigen density. As the huMNC2-CAR22 (1XX) trial proceeds, we will assess if patient responses mirror our animal results that show that the 1XX mutations confer increased persistence, reduced exhaustion and the ability to kill tumors with low antigen density. Citation Format: Cynthia Carol Bamdad, Joanne E. Mortimer, Yuan Yuan, Jennifer M. Specht, Andrew K. Stewart, Benoit J. Smagghe, Stephen C. Lin, Mark G. Carter, Tim W. Synold, Mark D. Fleming, Stanley R. Hamilton, Vishwas Parekh, Danica M. Walkley, Qing Liu-Michael, Kevin R. Yi, Jac-Leen S. Nash, Michael J. Nash, Stephen J. Forman. Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT096.

Complex association of body mass index and outcomes in patients with relapsed and refractory multiple myeloma treated with CAR-T cell immunotherapy

Background aimsChimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. MethodsWe conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. ResultsThe objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. ConclusionsOverall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis

Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS),including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases. Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS. CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection ofCD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64. CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19+ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted. Both individual treatments as well the generated data were not based on external funding.

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CAR-T demonstrates clinical efficacy for patients with RT.

Abstract 3192: A novel long acting pegylated T cell engager targeting CD3 and cd19 with effective tumor killing and no potential CRS risk in CD19+ hematologic malignancies

Abstract The development of bispecific T cell engagers represents a highly effective immunotherapy strategy for the treatment of hematologic malignancies. However, Blinatumomab, a bispecific T cell engager of CD3/CD19, has disadvantages in clinical setting due to the adverse pharmacokinetics (PK), which resulted in less than 2 hours of in vivo elimination half-life, neurotoxicity, and cytokine release syndrome. In this study, a bispecific antibody JY108 was developed to target CD19 and CD3e with much reduced affinities towards both targets (revealed by Biacore assay results). JY108 was prepared by a patented pegylation bispecific linker technology, which could address the limitations of current therapeutic approaches. In vitro cytotoxicity assay results demonstrated that the EC50s of the drug specific cytotoxicity of T cells mediated by JY108 are in the concentrations of ng/ml, while blinatumomab mediated cytotoxicity to the same CD19+ cells are in the concentrations of pg/ml. Despite the weaker in vitro cytotoxicity than Blinatumomab, JY108 presents comparable tumor inhibition effects with Blinatumomab in different in vivo studies, which include the PBMC reconstructed models with established MEC-1 or Farage tumors, the delayed drug administration on human PBMCs/tumor co-transplanted model of Raji. In addition, JY108 prolonged the survival of animals with Nalm6 brain metastasis more significantly than Blinatumomab at the same dosage. Furthermore, the PK study revealed that at the different dosages, the circulation T1/2s of JY108 in mice are above 20 hours, which is expected to result in more significant efficacious benefits in clinical setting. Meanwhile, the completed package of GLP-toxicity study did not observe any drug related tox to the model animals (including no cytokine release in vivo, no neurotoxicity, no respiratory toxicity, etc.), and JY108 did not induce significant cytokine release than the blank control to the whole blood or PBMCs from healthy donor in vitro. In the efficacious concentrations of exerting cytotoxicity to CD19+ tumor cells in the presence of PBMC, JY108 did not induce significant cytokine release than the blank control, while blinatumomab always induced significant cytokine release. We postulated that the lower CD3 affinity of JY108 most probably resulted in the decoupling of the signaling for activating the gene expression of cytokines from the secretion of the polarized lytic granules by T cells, which resulted in a much milder T cell activation by JY108. Currently, JY108 is a phase I trial candidate and awaits further evaluations. Citation Format: Shumin (Sam) Liu, Yu (Yvonne) Wen, Weidong Lyu, Shuqiang Yin, Yang Lei, Dechun Wu, Zibin Wu, Qiudong Zhuo. A novel long acting pegylated T cell engager targeting CD3 and cd19 with effective tumor killing and no potential CRS risk in CD19+ hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3192.

Abstract 7164: Exposure-efficacy and exposure-safety relationships of tarlatamab to inform dose selection and benefit-risk assessment in patients with advanced small cell lung cancer (SCLC)

Abstract Introduction: Tarlatamab is a first in class, half-life extended bispecific T-cell engager (BiTE) immunotherapy targeting delta-like ligand 3 (DLL3) that has shown promising anti-tumor activity and survival outcomes with manageable safety profile in clinical studies of patients with previously treated SCLC (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we characterized the exposure-efficacy and exposure-safety profiles associated with tarlatamab treatment in SCLC, including the effects of patient-specific covariates (brain or liver metastasis, smoking status, number of prior lines of therapy, prior PD-1/PD-L1 inhibitor therapy, sum of target lesion diameters, and presence of anti-drug antibody). Methods: The analysis dataset consisted of 412 subjects with SCLC from ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). Serum tarlatamab exposure averaged over the first cycle (28 days) was utilized as the predictor of response in the regression analysis. Efficacy endpoints included objective response rate, disease control rate, best tumor size response, progression-free survival and overall survival (OS). Safety endpoints included overall treatment related adverse event (TRAE), overall treatment emergent adverse event (TEAE), and TEAEs of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and associated neurologic events, and neutropenia. Only the grade ≥ 3 adverse events (AEs) were evaluated. Results: Significant exposure-response relationships were established for all key efficacy measures across the dose range investigated. Plateau in the exposure-efficacy relationship (maximal efficacy) was observed at the recommended dose of 10 mg Q2W. Exposures associated with lower doses were estimated to have lower efficacy. No clear trends for exposure-response relationships were identified for the evaluated AEs except for grade ≥ 3 neutropenia, where a shallow trend was observed for increased neutropenia rate with increasing tarlatamab exposures. Of all the evaluated covariate relationships, only higher baseline sum of target lesion diameters was statistically significantly correlated with worsening of OS. Conclusions: Overall results in this SCLC population suggest tarlatamab exposures associated with the recommended dose of 10 mg Q2W exhibited near maximal efficacy and a favorable benefit-risk profile. None of the evaluated patient-specific covariates resulted in clinically meaningful changes in efficacy or safety, and therefore do not warrant a dose adjustment. Citation Format: Po-Wei Chen, Mukul Minocha, Stephanie M. Kong, Erik S. Anderson, Amanda Parkes, Pablo Martinez, Brett E. Houk, Chih-Wei Lin. Exposure-efficacy and exposure-safety relationships of tarlatamab to inform dose selection and benefit-risk assessment in patients with advanced small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7164.

Abstract 3993: A tunable safety switch for solid tumor CAR T-cell therapy

Abstract On-target off-tumor toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) are severe immune-related adverse events (irAEs) that are frequently associated with Chimeric Antigen Receptor (CAR) T-cell therapy. Current efforts to manage such therapy-related toxicities involve incorporation of an inducible suicide agent within CAR constructs, such as iCaspase-9 or herpes simplex virus type 1 thymidine kinase that can be selectively activated to produce toxic effects within CAR T cells and attenuate their activity. However, while activation of these agents helps to mitigate or overcome such unwarranted toxicities, the therapeutic benefit of CAR T cells anti-tumor activity is also compromised. Therefore, to continue maintenance of CAR T cells’ therapeutic function while minimizing irAEs, an ideal safety switch should 1) rapidly inhibit the activation and proliferation of CAR T cells exposed to the target antigen, 2) reversibly inhibit activity without inducing CAR T cell elimination and 3) be clinically translatable for safe application in patients. Our laboratory investigated one such safety switch to inhibit CAR T-cell activity while maintaining their therapeutic function. We showed that incorporating a mutant variant of c-KIT D816V (KITv) in the intracellular domain of mesothelin-targeting second-generation CAR T cells (M28z-KITv) improved efficacy in solid tumors with low antigen, or an immunosuppressive environment. Herein, we evaluate the use of Dasatinib, a clinically available multitarget (BCR, SRC, c-KIT) tyrosine kinase inhibitor (TKI), as a tunable safety switch to reversibly inhibit M28z-KITv CAR T-cell functional activity. In cohorts of mice established with lung adenocarcinoma, daily administration of Dasatinib starting on day 1 or day 3 after CAR T-cell administration stabilized tumor growth, which otherwise continued to regress in untreated mice, indicating inhibition of CAR T-cell functional activity. Upon discontinuation of Dasatinib, tumors regressed, indicating reversal of CAR T-cell functional activity. In an experiment conducted to investigate functional persistence of CAR T cells upon long-term exposure to Dasatinib (1 month), we noted uninhibited activity of CAR T cells to rechallenged tumors. Dasatinib, thus may act as a tunable safety switch to regulate M28z-KITv CAR T-cell activity without compromising its therapeutic function. Citation Format: Kyohei Misawa, Meriem Taleb, Srijita Banerjee, William-Ray Vista, Navin K. Chintala, Prasad S. Adusumilli. A tunable safety switch for solid tumor CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3993.

Abstract 3616: In vivo expansion patterns of anti-BCMA CAR T-cell in relapsed/refractory multiple myeloma: Comparative immunomonitoring of idecabtagene vicleucel and ciltacabtagene autoleucel

Abstract Introduction: Chimeric antigen receptor (CAR) T cell (CAR-T) treatments have revolutionized the treatment of multiple myeloma (MM). Two CAR-T cell products targeting B cell maturation antigen (BCMA) have received approval for the treatment of MM: idecabtagene vicleucel (idecel) and ciltacabtagene autoleucel (ciltacel). A comparative analysis of in vivo CAR-T responses in patients receiving these novel cellular therapies has not been performed, especially not in the real-world setting. Methods: We prospectively enrolled 23 MM patients treated with idecel or ciltacel in our study GCCC2043. Blood samples were obtained at apheresis, pre-lymphodepleting (LD) chemotherapy, on days 0, +7, +14, +21, +28 and at +3 months post CAR-T. Samples were stained using BCMA or control CAR detection reagents, monoclonal antibodies against T cell surface antigens, and analyzed using flow cytometry. Results: Baseline clinical characteristics, pre-apheresis and pre-LD absolute lymphocyte counts were comparable between groups. There were no G3 cytokine release syndrome (CRS) events whereas G1/2 CRS and all-grade Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) events were not significantly different between cohorts. The global overall response rate (ORR) was 78.3% (n=18) and 60.9% (n=14) at days 30 and 90, respectively. At +1 month, 72.7% (8/11) of idecel and 83.3% (10/12) of ciltacel cohort had an objective response (p=0.625). There was no statistical ORR difference between idecel and ciltacel cohorts at 3, 6, and 9 months. Two-way ANOVA of CAR-T expansion studies revealed a trend towards an effect of treatment type (p=0.0595). Time to peak CAR-T numbers was significantly shorter for idecel (p=0.0127), however, ciltacel showed a significantly more pronounced CAR-T expansion (p=0.043) and longer persistence. Peak CAR-T expansion was associated with clinical responses across cohorts at +1 (p=0.034) and +3 months (p=0.050). Day +30 responses were indicative of Day +90 and Day +180 responses (p<0.001, p=0.011). There was no difference in CD8+ CAR T cell peak levels, however, CD4+ CAR T cell peak levels were much higher (p=0.019) for ciltacel vs. idecel. Similarly, there were significantly higher (p=0.002) CD4+/CD8+ double-positive CAR-T peak levels in ciltacel vs. idecel patients. There was no significant difference in the distribution of T cell memory subtypes at peak level. Conclusions: We demonstrate here for the first time significant differences in CAR T cell expansion and persistence patterns following infusion of either idacel or ciltacel. Studies are underway at our institution investigating anti-BCMA CAR T cell responses in more detail and larger numbers of patients. Such studies have the potential to identify predictive/prognostic biomarkers and/or lead to further optimization of myeloma-targeting CAR-T. Citation Format: Mehmet Kocoglu, Aaron P. Rapoport, Etse Gebru, Destiny Omili, Daniel Yamoah, Rediet Mulatu, Jean Yared, Nancy M. Hardy, Michael Kallen, Ashraf Z. Badros, Djordje Atanackovic. In vivo expansion patterns of anti-BCMA CAR T-cell in relapsed/refractory multiple myeloma: Comparative immunomonitoring of idecabtagene vicleucel and ciltacabtagene autoleucel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3616.