CAR-T Cell Treatment Research Articles

Talquetamab in Multiple Myeloma: Efficacy, Safety, and Future Directions.

Relapsed and refractory multiple myeloma (RRMM) remains a challenging condition despite advances in immunotherapies. Novel bispecific antibodies (BsAbs), including talquetamab, have shown promising efficacy in heavily pretreated patients, even those with triple- and penta-refractory disease. Talquetamab, recently approved by the FDA and EMA, is indicated for patients who have progressed after at least three or four prior lines of therapy (LOTs). Administered following a step-up dosing phase to manage cytokine release syndrome (CRS), talquetamab demonstrated a high overall response rate (ORR) of approximately 70%, including in patients previously treated with T-cell redirecting therapies. Its safety profile is consistent with other BsAbs, with hematologic adverse events such as anemia and neutropenia commonly reported, alongside unique on-target off-tumor toxicities like dysgeusia and skin-related events. Infections were less frequent compared to other BsAbs. The optimal sequencing of talquetamab and other therapies, including CAR-T cell treatments, remains an area of active research, as resistance to anti-BCMA therapies presents ongoing clinical challenges. Current trials are exploring the use of talquetamab in combination therapies, as well as therapeutic strategies post-treating progression. The real-world data further support talquetamab's efficacy, making it a valuable addition to the RRMM treatment landscape.

Advances in Primary Central Nervous System Lymphoma.

Optimal initial management can have a significant impact in long-term outcome in primary CNS lymphoma. This article reviews recent advances and the state of the field. Genomic analysis of CSF cell-free DNA has emerged as a new diagnostic tool for PCNSL. Treatment options have likewise evolved, with mature data from first-line chemotherapy-based prospective trials disclosing excellent results in younger (< 60-65) patients, with a cure achieved in a majority. However, results in older patients remain dismal, with several new salvage options under investigation including BTK pathway-targeted therapies, and CAR-T cell treatments. Meanwhile, low-dose radiation has emerged as an additional alternative for consolidation therapy. For younger PCNSL patients, the goal of treatment is now a cure, with the next frontier being the development of therapies affording optimized neurocognitive outcome and lower toxicity. Treatment for older patients remains however an unmet need, with several promising clinical trials ongoing.

GVHD after CAR T-cell therapy post allogeneic hematopoietic cell transplantation - successfully treated by extracorporeal photopheresis.

CAR T-cell therapy is highly effective, but also associated with unique toxicities. Because of the origin of T cells in patients who previously underwent allogeneic hematopoietic cell transplantation (alloHCT), graft-versus-host disease (GVHD) in the post-CAR T-cell setting poses a relevant concern but is only scarcely studied. Potential risk factors and mitigation strategies (from CAR T-cell modifications to clinical management) are yet to be determined. Sharing our retrospective experience and a mini-review of the literature, our aim is to better understand the frequency and risk of the potential occurrence of GVHD after CAR T cells, which are most likely underestimated. Here, we present a cohort of 11 patients with symptoms suggestive of GVHD out of 25 allografted patients treated with CAR T cells, of whom 3 patients (12%) had GVHD most likely triggered by the preceding CAR T-cell treatment. Severe chronic pulmonary GVHD occurred in a patient after CD19-directed CAR T-cell therapy. Extracorporeal photopheresis (ECP) mediated successful long-term control of GVHD without causing relapse of the underlying disease. In conclusion, CD19-directed CAR T-cell therapy seems to be feasible in patients after alloHCT but might comprise the potential risk of triggering GVHD, most likely depending on the T-cell source, donor compatibility, and the specific CAR construct used.

TMOD-02. PATIENT-DERIVED GLIOBLASTOMA ORGANOIDS AS REAL-TIME AVATARS FOR ASSESSING RESPONSES TO CLINICAL CAR-T CELL THERAPY

Abstract Patient-derived tumor organoids have been increasingly leveraged for disease modeling and preclinical studies, but rarely in real-time to aid with the interpretation of patient treatment responses in the clinical setting. Whether tumor organoids can be applied to mirror clinical activity in patients and even to predict responses for personalized medicine remains uncertain. We recently demonstrated promising early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma (clinical trial identifier: NCT05168423). Determination of meaningful clinical efficacy, in particular for CAR-T cell therapy, may take months to manifest. Given this challenge, real-time analysis of patient-derived glioblastoma organoids (GBOs) could help to provide early assessment of clinical efficacy and guide patient management. We analyzed six sets of GBOs generated on the same timeline as the production of patients’ CAR-T cell products. GBOs demonstrated the presence and retention of both targeted tumor-associated antigens EGFR and IL13Rα2 by immunohistochemistry. These GBOs were then treated with the same autologous CAR-T cell products received by patients in our phase 1 study in parallel with patient treatment. CAR-T cell treatment led to target antigen reduction assessed by immunohistochemistry and flow cytometry. Furthermore, we confirmed cytolysis of tumor cells in GBOs by cleaved caspase-3 immunostaining and by co-culture in the Axion Maestro Cellular Impedance platform. Importantly, the degree of cytolysis ex vivo significantly correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF) for all six patients. Furthermore, cytotoxic activity of CAR-T cells as measured by TNFα, IL-2, and IFNγ release kinetics in GBOs mirrored cytokine levels in patient CSF samples over time. Our findings highlight a unique trial design and suggest GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and for insights into immunotherapy efficacy.

Cancer cachexia and weight loss before CAR T-cell therapy for lymphoma are independently associated with poor outcomes

AbstractChimeric antigen receptor (CAR) T-cell therapy has transformed the care of lymphoma, yet many patients relapse. Several prognostic markers have been associated with CAR T-cell outcomes, such as tumor burden, response to bridging chemotherapy, and laboratory parameters at the time of lymphodepletion or infusion. The effect of cancer cachexia and weight loss before CAR T cells on toxicity and outcomes is not well understood. Here, we present a retrospective single-institution cohort study of 259 patients with lymphoma treated with CAR T cells between 2017 and 2023. We observed that patients with >5% decrease in their body mass index in the 3 months preceding CAR T-cell treatment (weight loss group; all meeting one of the commonly accepted definitions of cancer cachexia) had higher disease burden and inflammatory parameters (C-reactive protein, ferritin, interleukin-6, and tumor necrosis factor α) at the time of lymphodepletion and CAR T-cell infusion. Patients with weight loss experienced higher rates of grade 3+ neurotoxicity and early hematotoxicity, but those effects were not seen upon multivariable adjustment. However, in both univariate and multivariable analysis, patients with weight loss had worse response rates, overall survival, and event-free survival, indicating that weight loss is an independent poor prognostic factor. Our data suggest that weight loss in the 3 months preceding CAR T-cell therapy represents a worrisome “alarm signal” and a potentially modifiable factor, alongside tumor burden and inflammation, and warrants further investigation in patients treated with CAR T-cell therapy.

CD19-targeting CAR-T cell treatment in patients with diffuse systemic sclerosis

CD19-targeting CAR-T cell treatment in patients with diffuse systemic sclerosis

Real-world outcomes of commercial tisagenlecleucel for children, adolescents, and young adults with acute lymphoblastic leukemia in Japan

Background: Chimeric antigen receptor (CAR) T cells are a major new treatment option for children, adolescents, and young adults (CAYA) patients with relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Therefore, accumulating evidence from real-world experiences of CAR-T outcomes in various regions world-wide is important, particularly when comparing outcomes of patients with differing medical and ethnic backgrounds.Objective: More than 5 years have passed since tisagenlecleucel was approved in Japan. Here, we report a retrospective, multi-institutional investigation examining the association between baseline parameters and clinical outcomes. The aim was to investigate real-world experience, and to better comprehend the efficacy of commercial tisagenlecleucel.Study Design: A nationwide consortium called the Japan CAR-T Consortium conducted a retrospective, multicenter study of CAYA patients who received CAR-T cell treatment with commercial tisagenlecleucel. Forty-two patients with R/R B-ALL whose leukapheresis samples were shipped to Novartis for commercial tisagenlecleucel manufacture were included in the analysis. All infused patients were included in the response, toxicity, and survival analyses.Results: The best overall response rate was 93%. The 1-year overall survival (OS) and event-free survival (EFS) rates after infusion were 82% and 56%, respectively. Twenty-seven (64%) had low disease burden (LB, defined as <5% bone marrow [BM] lymphoblasts) prior to tisagenlecleucel infusion. LB was associated with superior outcomes, with a 1-year EFS rate of 80% compared with 24% in high disease burden (≧5% BM lymphoblasts). Multivariate analysis identified an association between prior hematopoietic stem cell transplantation (HSCT) (n=23, 55%) and superior outcomes, with a 1-year EFS rate of 75% compared with 24% for patients without prior HSCT.Conclusion: This first analysis of CAYA patients with R/R B-ALL undergoing treatment with commercial tisagenlecleucel in Japan reports an efficacy similar to that in clinical trials and other real-world studies and confirms that LB and prior HSCT are associated with superior EFS.

IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy

Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4+ Tcell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR Tcell treatment on LSCs invitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.

IL-12 encoding oNDV synergizes with CAR-T cells in orthotopic models of non-small cell lung cancer

Systemic administration of oncolytic viruses (OVs) is a promising approach for targeting metastatic solid tumors, but their anti-tumor activity is limited by pre-existing neutralizing antibodies against common human viruses. Therefore, investigators have developed OVs derived from non-human host viruses. Successful implementation of this strategy requires that the viral vector selectively infects and replicates within human cancer cells. Newcastle disease virus (NDV) is an avian paramyxovirus that as NDV-based OVs (oNDVs) have demonstrated safety and activity against multiple human tumors in clinical trials. Their use as a single agent, however is insufficient to cure tumors. Similarly, CAR-T cells enable systemic targeting of cancer cells but have limited anti-tumor effects against bulky solid tumors, in part due to the immunosuppressive tumor environment. In this study, we evaluated the anti-tumor effects of combining systemic oNDV and CAR-T cell treatments. In models of non-small cell lung carcinoma (NSCLC), we found that oNDV itself and IL-12 derived from oNDV enhance HER2-directed CAR-T cell anti-tumor activity and persistence in vitro and in vivo, leading to superior control of NSCLC tumors compared with either agent alone in vivo. Our data indicate that oNDV enhances the anti-tumor effects of HER2.CAR-T cells, thus controlling the growth of orthotopic NSCLC tumors.

High-Dose Chemotherapy and Autologous or Allogeneic Transplantation in Aggressive B-Cell Lymphoma-Is There Still a Role?

Novel therapies such as CAR-T, BTK inhibitors and PD-1 inhibitors have changed the management of aggressive B-cell lymphomas. Nonetheless, these novel therapies have their own risk of late toxicities including second malignancies. They also create a subgroup of patients with relapse, treatment failure, or indefinite maintenance. We discuss the current role of autologous and allogeneic stem cell transplantation in this context. In patients with recurrent diffuse large B-cell lymphoma, CAR-T cell treatment has largely replaced autologous transplant. Autologous transplant should be considered in patients with late relapses and in selected patients with T-cell-rich B-cell lymphoma, where CAR-T cell therapy may be less effective. It also remains the treatment of choice for consolidation of patients with primary CNS lymphoma. In mantle cell lymphoma, intensive chemotherapy combined with BTK inhibitors and rituximab results in excellent outcomes, and the role of autologous transplantation is declining. In Hodgkin's lymphoma, autologous transplant consolidation remains the standard of care for patients who failed initial chemotherapy. Allogeneic transplantation has lower relapse rates but more complications and higher non-relapse mortality than autologous transplantation. It is usually reserved for patients who fail autologous transplantation or in whom autologous stem cells cannot be collected. It may also have an important role in patients who fail CAR-T therapies. The increasing complexity of care and evolving sequencing of therapies for patients with aggressive B-cell lymphomas only emphasizes the importance of appropriate patient selection and optimal timing of stem cell transplantation.

Emerging Role of CAR-T Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a malignant clonal disease originating from hematopoietic stem cells. In the past few decades, AML treatment has been dominated by a "3+7" regimen (anthracyclines + cytarabine), and the survival curve has stagnated. However, these procedures are associated with serious adverse effects. The development of chimeric antigen receptor (CAR)-T cell treatment provides a viable alternative, with decreased non-relapse death rates. Despite its potential, CAR-T cell therapy for AML confronts significant obstacles due to the disease's heterogeneity and accompanying toxicity. Genetic alteration strategies are being investigated to improve its safety and efficacy. Engineering CAR-T cells to express inhibitory receptors or suicide genes can help regulate T cell activity and prevent excessive immune activation. In summary, while CAR-T cell treatment has promise for AML, overcoming its hurdles through genetic modification and target refining is crucial. This review focuses on the existing landscape and future directions of CAR-T cell treatment for AML.

Dual CAR-T cell therapy for glioblastoma: strategies to cure tumour diseases based on a mathematical model

AbstractThe CAR-T cell immunotherapy entails the genetic reprogramming of T-lymphocytes, which then engage with cancer cells, triggering an anti-tumour immune response. While this treatment has gained approval for hematological cancers, addressing solid tumours presents new obstacles. Challenges include the heterogeneity of antigen expression within solid tumours, encompassing antigen-positive non-tumoural cells, the presence of immune inhibitory molecules, and the difficulty of CAR-T cell trafficking within the tumour microenvironment. In this article, we analytically study a generalisation of a mathematical model proposed by León-Triana et al. (Cancers 13(4):703, 2021a. https://doi.org/10.3390/cancers13040703, Commun Nonlinear Sci Numer Simul 94:105570). This model focuses on the dynamics of glioblastoma, the most aggressive brain tumour, and its response to CAR-T cell treatment. We study the basic properties of the model, the dynamics of the solutions of the model when the treatment is not sustained during the time, and finally we study analytically the model when the therapy is constant, periodic and/or impulsive. We derive sufficient conditions for global stability of tumour-free equilibrium, as well as necessary and sufficient conditions for local stability of the equilibrium obtaining conditions for an effective treatment. Finally, we perform different numerical simulations to find the strategies to keep the tumour under control. The obtained results are based on a combination of different analytical techniques in differential equations, dynamical systems and numerical simulations.

Évaluation en vie réelle du parcours de soins des patients éligibles à un traitement par axicabtagene ciloleucel : cohorte multicentrique IMPA-CT

The arrival of CAR-T cell treatments in Europe in 2018 has considerably changed the clinical and logistical management of lymphoma patients. The aim of this study is to evaluate pathways of patients eligible for axicabtagene ciloleucel (axi-cel), particularly previously and afterwards of its administration, stages that are currently poorly documented in the literature. Ninety-eight patients from eleven French qualified centers eligible for axi-cel treatment between June 2020 and February 2021 were retrospectively included. Of all the stages in the care pathway evaluated, the median time observed between relapse after the previous line and prescription of axi-cel was 27days, and the median time between the multidisciplinary consultation meeting and axi-cel administration was 63days. The two main methods of discharge from hospital were a return home (65% of cases) or hospitalisation in a rehabilitation unit (20% of cases). Among all the geographical and organizational characteristics assessed, no factor was found to have a significant impact on the time length of the patient's journey, apart from the patient capacity of the qualified center, and the origin of the patient's referral (coming from a qualified or a referral center). Since the study was carried out, the number of qualified centers has continued to rise, improving territorial coverage and access to treatment.

CD19-Directed CAR T-Cells in a Patient With Refractory MOGAD: Clinical and Immunologic Follow-Up for 1 Year.

In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells. CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis and infused after a conventional lymphodepleting regimen. A 18-year-old man developed 2 episodes of myelitis associated with serum MOG-IgG, which were followed by 6 episodes of left optic neuritis (ON) and sustained the presence of MOG-IgG over 6 years despite multiple immunotherapies. After the sixth episode of ON, accompanied by severe residual visual deficits, CAR T-cell treatment was provided without complications. Follow-up of cell counts showed complete depletion of CD19+ B cells at day +7; reconstituted B cells at day +141 showing a naïve B-cell phenotype, and low or absent memory B cells and plasmablasts for 1 year. MOG-IgG titers have remained undetectable since CAR T-cell infusion. The patient had an early episode of left ON at day +29, when MOG-IgG was already negative, and since then he has remained free of relapses without immunotherapy for 1 year. This clinical case shows that CD19-directed CAR T-cell therapy is well-tolerated and is a potential treatment for patients with refractory MOGAD. This provides Class IV evidence. It is a single observational study without controls.

Revolutionizing Immunotherapy: Unveiling New Horizons, Confronting Challenges, and Navigating Therapeutic Frontiers in CAR-T Cell-Based Gene Therapies.

The CAR-T cell therapy has marked the dawn of new era in the cancer therapeutics and cell engineering techniques. The review emphasizes on the challenges that obstruct the therapeutic efficiency caused by cell toxicities, immunosuppressive tumor environment, and decreased T cell infiltration. In the interest of achieving the overall survival (OS) and event-free survival (EFS) of patients, the conceptual background of potential target selection and various CAR-T cell design techniques are described which can minimize the off-target effects, reduce toxicity, and thus increase the resilience of CAR-T cell treatment in the haematological malignancies as well as in solid tumors. Furthermore, it delves into cutting-edge technologies like gene editing and synthetic biology, providing new opportunities to enhance the functionality of CAR-T cells and overcome mechanisms of immune evasion. This review provides a comprehensive understanding of the complex and diverse aspects of CAR-T cell-based gene treatments, including both scientific and clinical aspects. By effectively addressing the obstacles and utilizing the capabilities of cutting-edge technology, CAR-T cell therapy shows potential in fundamentally changing immunotherapy and reshaping the approach to cancer treatment.

CAR-T Cells Therapy in Glioblastoma: A Systematic Review on Molecular Targets and Treatment Strategies.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.

Abstract PO-001: GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance

Abstract Chimeric antigen receptor (CAR)-T cell therapies can be curative for CD19+ hematological malignancies, though are limited by frequent patient relapse and response failures. Here, we identify GPR65 as a tumor-specific determinant of responsiveness to CAR-T cell therapy. In patients and an immune competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) response to CAR-T cell therapy, high GPR65 is associated with a complete tumor response. In mice, GPR65 knockout (GPR65 KO) tumors are resistant to CAR-T cell therapy in vivo, without antigen loss. Single-cell network analyses reveal that GPR65 deficiency remodels tumor interactions with host macrophages, partially through increasing tumor VEGFA. This leads to increased macrophage numbers and preferential M2 macrophage polarization. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restores responsiveness to CAR-T cell treatment. Anti-VEGFA therapy in combination with CAR-T cell administration also prolongs the survival of GPR65 KO tumor-bearing mice. Our results indicate that tumor GPR65 expression is important for B-ALL responses to CAR-T cell therapy through its impact on the tumor microenvironment and supports new approaches to identify and overcome CAR-T cell resistance. Citation Format: Jayadev Mavuluri. GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-001.

The Fate(s) of CAR T-Cell Therapy: Navigating the Risks of CAR+ T-Cell Malignancy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy represents a landmark advancement in treating resistant forms of cancer such as leukemia, lymphoma, and myeloma. However, concerns about long-term safety have emerged following an FDA investigation into reports of second primary malignancies (SPM) after CAR-T cell treatment. This review offers a thorough examination of how genetically modified T cells might transform into CAR+ SPM. It explores genetic and molecular pathways leading to T-cell lymphomagenesis, the balance between CAR T-cell persistence, stemness, and oncogenic risk, and the trade-off of T-cell exhaustion, which may limit therapy efficacy but potentially reduce lymphomagenesis risk. Significance: An FDA probe into 22 cases of second primary T-cell malignancies following CAR T-cell therapy stresses the need to investigate their origins. Few may arise from preexisting genetic and epigenetic alterations and those introduced during therapeutic engineering. Technological advances, regulatory oversight, and patient monitoring are essential to mitigate potential risks.

Influence of gender on acute kidney injury among patients undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy: Insights from National Inpatient Sample.

e14524 Background: Chimeric antigen receptor T-cell (CAR-T Cell) immunotherapy has shown promising results in patients with B-cell leukemia and lymphoma and multiple myeloma. The side effect profile is still being studied and acute kidney injury (AKI) following treatment has been a commonly reported outcome in the context of cytokine release syndrome. In most cases, the kidney injury is reversible with adequate hydration and treatment of the underlying cytokine release syndrome when needed. This study aimed to investigate the outcomes of gender in patients undergoing CAR-T cell therapy along with the protective variables and independent predictors of AKI in this patient population. Methods: This was a retrospective analysis of data the National Inpatient Sample (NIS) between January 2019 and December 2020 to identify patients who underwent CAR-T cell therapy. We stratified the data based on gender and studied the incidence of AKI in patient admitted to the hospital primarily for CAR-T cell treatment. The primary endpoint was in-hospital mortality, AKI, average age, length of stay (LOS), and total charge by hospital. Additionally, we explored independent predictors and protective variables for AKI in patients receiving the treatment. Results: A total of 4010 patients underwent CAR-T Cell therapy from January 2019 to December 2020. Among these patients, females comprised 41.1% (n=1650). The mean age at the time of CAR-T cell treatment for males was 57.5 and for females 56.9. The inpatient mortality rates for both groups were 3% (p=0.97). The total incidence of AKI in patients undergoing CAR-T cell therapy was 14.9%, with rates of 19% in males and 9% in females (p&lt;0.01). LOS for males and females was 19 days, and 20 days respectively (p=0.4). Average total hospital charge for males was 958,345 and 1,017,685 for females (p=0.3642). Interestingly, there was no difference between genders in relation to the incidence of cytokine release syndrome (p=0.3). Notably, CKD, obesity, liver disease, and electrolyte imbalances were independent predictors of AKI with an adjusted odds ratio of 4.26 (p&lt;0.01; 95% confidence interval [CI]: 1.7-10.6), 2.7 (p=0.015; 95% CI: 1.2-6.06), 2.7 (p=0.045; 95% CI: 1.02-7.23), 2.5 (p&lt;0.01; 95% CI: 1.67-3.81). Importantly, gender was a protective variable for females when it came to AKI after CAR-T cell therapy with an adjusted odds ratio of 0.38 (p&lt;0.01; 95% CI: 0.23-0.63). Conclusions: AKI has been documented as a common side effect in patients undergoing CAR-T cell therapy. In most cases the kidney injury is reversible with adequate hydration and CRS treatment when necessary. Our study highlights CKD, obesity, liver disease, and electrolyte imbalance as independent predictors of AKI after CAR-T cell therapy and female gender as a predictive variable against developing AKI.

Phase I clinical trial of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of advanced breast cancer.

1089 Background: In the treatment of breast cancer, the therapeutic efficacy of CAR-T cell therapy remains unsatisfactory. A possible approach to enhance the efficacy of CAR-T therapy is to combine CAR-T with PD-1 inhibition. This clinical trial was designed to assess the safety and tolerability of PD-1 knockout MUC1-targeted CAR-T cells in advanced breast cancer. Methods: Patients with advanced breast cancer were recruited according to the criteria in NCT05812326. PD-1 gene knockout (KO) MUC1-targeted CAR-T cells were prepared in 2 steps. MUC1-specific CARs were first constructed using 5E5 scFv in patient-derived T cells, and then PD-1 gene KO was achieved in these CAR positive T cells using the CRISPR-Cas9 system. Efficiency and validation were confirmed by sequencing and flow cytometry. MUC1-CAR+/PD-1-T cells were infused at a starting dose of 1-2x106 CAR+ cells/kg and then escalated to 0.9-1.8x107 CAR+ cells/kg. The safety and tolerability of therapeutic cells were evaluated using CTCAE v5.0. Patients’ general condition, levels of lymphocytes, and serum cytokines (IL-1β, IL-2R, IL-6, IL-8, TNF and IL-10) were monitored. Circulating CAR-T cells were checked regularly. Changes in tumor size were examined by MRI/CT scans. The primary endpoint was to assess the safety of this treatment. We also compared the responses in patients who received single and multiple cycles of infusion of therapeutic CAR-T cells. Results: A total of 12 patients (aged 34 to 61) diagnosed with recurrent/metastatic breast cancer were included in this study. All participants received at least 1 cycle of CAR-T cell treatment. Among the 12 patients, 8 received 1 cycle, 3 received 2 cycles, 1 received 3 cycles. Adverse events (AEs) included elevated AST level (7/12, 58.3%), acute fever (6/12), elevated ALT level (5/12), skin rash (5/12), chills (4/12), anemia (4/12), lymphopenia (4/12), diarrhea, vomiting and urinary tract infection (2/12). The most serious AE was lymphopenia (grade 4 lasting 1 day in 1 patient). No grade 3-5 CRS was observed. No patients experienced neurotoxicity. No predefined dose-limiting toxicities (DLT) or serious AEs were observed. Furthermore, there were no AEs resulting in discontinuation of treatment. Of the 12 patients evaluated, 5 had stable disease (SD), indicating that MUC1 CAR-T cell therapy can control the progression of some advanced breast cancers, despite the fact that the efficacy assessment is quite preliminary. The pharmacokinetic study indicated that improved clinical outcomes are associated with a high level of circulating CAR+ copy on day 7. Conclusions: Our data suggest that treatment of patients with advanced breast cancer with PD-1 disrupted MUC1-targeted CAR-T cells is safe and well-tolerated by all patients in this phase 1 clinical trial. No serious CRS or other EA was observed throughout the study. The efficacy of this unique combined therapy is currently being assessed. Clinical trial information: NCT05812326 .