Chimeric Antigen Receptor Research Articles

Incidence of preexisting B-cell aplasia in B-ALL: implications for post–CAR T-cell monitoring

Ongoing B-cell aplasia (BCA) post-CAR T-cell infusion is increasingly utilized as a surrogate for functional CAR T-cell persistence in patients with relapsed/refractory B-ALL. We sought to evaluate the incidence of pre-treatment BCA—which may impact post-infusion BCA monitoring.

Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview.

The protein tyrosine kinase-7 (PTK7) is an evolutionarily conserved transmembrane receptor that has emerged as a potential therapeutic target for human tumors. PTK7 is a pseudokinase that is involved in the modulation of the Wnt signaling pathway through interactions with other receptors. These interactions result in targeted gene activation that regulates cell polarity, migration, and proliferation during embryogenesis. Aside of this role during development, PTK7 has been shown as overexpressed in numerous cancers including colon carcinoma, leukemia, neuroblastoma, hepatoma, and ovarian cancer. The activity of PTK7 and the direct correlation with poor prognosis have fostered preclinical investigations and phase I clinical trials, aiming at inhibiting PTK7 and inducing antitumoral effects. In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

CAR Treg synergy with anti-CD154 mediates infectious tolerance to dictate heart transplant outcomes.

Successful allograft specific tolerance induction would eliminate the need for daily immunosuppression and improve post-transplant quality of life. Adoptive cell therapy with regulatory T cells expressing donor-specific Chimeric Antigen Receptors (CAR-Tregs) is a promising strategy, but as monotherapy, cannot prolong the survival with allografts with multiple MHC mismatches. Using an HLA-A2-transgenic haplo-mismatched heart transplantation model in immunocompetent C57Bl/6 recipients, we show that HLA-A2-specific (A2) CAR Tregs was able to synergize with low dose of anti-CD154 to enhance graft survival. Using haplo-mismatched grafts expressing the 2W-OVA transgene and tetramer-based tracking of 2W- and OVA-specific T cells, we showed that in mice with accepted grafts, A2.CAR Tregs inhibited endogenous non-A2 donor- specific T cell, B cell and antibody responses, and promoted a significant increase in endogenous FoxP3 + Tregs with indirect donor-specificity. By contrast, in mice where A2.CAR Tregs failed to prolong graft survival, FoxP3 neg A2.CAR T cells preferentially accumulated in rejecting allografts and endogenous donor-specific responses were not controlled. This study therefore provides the first evidence for synergy between A2.CAR Tregs and CD154 blockade to promote infectious tolerance in immunocompetent recipients of haplo-mismatched heart grafts and defines features of A2.CAR Tregs when they fail to reshape host immunity towards allograft tolerance.

Expression features of targets for anti-glioma CAR-T cell immunotherapy

Expression features of targets for anti-glioma CAR-T cell immunotherapy

Comparative Analysis of Bispecific Antibodies and CAR T-Cell Therapy in Follicular Lymphoma.

The treatment landscape for relapsed/refractory follicular lymphoma (RR-FL) is marked by a pivotal debate between chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs). While both CAR-T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA-5 study, underscore axicabtagene ciloleucel (axi-cel)'s efficacy in treating RR-FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso-cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR-FL patients. Thus, CAR-T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost-effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost-effectiveness considerations are essential; while CAR-T therapies incur higher initial costs, their potential for long-term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR-FL management strategies.

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.

In Vitro Assessment of Thermo-Responsive Scaffold as a 3D Synthetic Matrix for CAR-T Potency Testing Against Glioblastoma Spheroids.

Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated exceptional efficacy against hematological malignancies, but notably less against solid tumors. To overcome this limitation, it is critical to investigate antitumor CAR-T cell potency in synthetic 3D microenvironments that can simulate the physical barriers presented by solid tumors. The overall goal of this study was the preliminary assessment of a synthetic thermo-responsive material as a substrate for invitro co-cultures of anti-disialoganglioside (GD2) CAR-T cells and patient-derived glioblastoma (GBM) spheroids. Independent co-culture experiments demonstrated that the encapsulation process did not adversely affect the cell cycle progression of glioma stem cells (GSCs) or CAR-T cells. GSC spheroids grew over time within the terpolymer scaffold, when seeded in the same ratio as the suspension control. Co-cultures of CAR-T cells in suspension with hydrogel-encapsulated GSC spheroids demonstrated that CAR-T cells could migrate through the hydrogel and target the encapsulated GSC spheroids. CAR-T cells killed approximately 80% of encapsulated GSCs, while maintaining effective CD4:CD8 T cell ratios and secreting inflammatory cytokines after interacting with GD2-expressing GSCs. Importantly, the scaffolds also facilitated cell harvesting for downstream cellular analysis. This study demonstrated that a synthetic 3D terpolymer hydrogel can serve as an artificial scaffold to investigate cellular immunotherapeutic potency against solid tumors.

Targeting CD5 chimeric antigen receptor-engineered natural killer cells against T-cell malignancies

BackgroundChimeric antigen receptor engineered T cells (CAR-T) have demonstrated promising clinical efficacy in B-cell malignancies, and the approach has been extended to T-cell malignancies. However, the use of allogeneic T cells in CAR therapy poses a challenge due to the risk of graft-versus-host disease. Recently, natural killer (NK) cells have exhibited “off‑the‑shelf” availability. The nanobody-based CAR structures have attracted much attention for their therapeutic potential owing to the advantages of nanobody, including small size, optimal stability, high affinity and manufacturing feasibility. CD5, a common surface marker of malignant T cells, has three scavenger receptor cysteine-rich domains (D1-D3) in the extracellular region. The present study aims to construct “off‑the‑shelf” CAR-NK cells targeting the membrane-proximal domain of CD5 derived from nanobody against T-cell malignancies.MethodsAnti-CD5-D3 nanobody was screened by phage display technology, followed by constructing fourth-generation CAR plasmids ectopically producing IL-15 to generate CD5 CAR-NK cells derived from peripheral blood. And the second-generation CD5 CAR-T cells based on nanobody were generated, referred to as 5D.b CAR-T and 12 C.b CAR-T. Furthermore, CAR-NK cells without IL-15 (IL-15△ CAR-NK) were generated to assess the impact on cytotoxicity of CAR-NK cells. Cytotoxic activity against CD5+ hematologic malignant cell lines and normal T cells was exerted in vitro and NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mouse model transplanted with Jurkat-Luc cells was used to evaluate the antitumor efficacy of CD5 CAR-NK cells in vivo.ResultsTwo nanobodies (5D and 12 C) competed for binding to the epitope of CD5-D3. 12 C CAR-NK cells were superior to 5D CAR-NK cells in antitumor potential and 12 C.b CAR-T cells exhibited superior cytotoxic activity than 5D CAR-T cells ex vivo. So, 12 C was regarded as the optimal nanobody. 12 C CAR-NK cells and IL-15△ CAR-NK cells exhibited robust cytotoxicity against CD5+ malignant cell lines and controlled disease progression in xenograft mouse model. 12 C CAR-NK cells demonstrated greater antitumor activity compared to that of IL-15△ CAR-NK cells in vitro and in vivo.ConclusionsTaken together, the fourth-generation nanobody-derived anti-CD5 CAR-NK cells may be a promising therapeutic against T-cell malignancies.

Targeting cardiac fibrosis with Chimeric Antigen Receptor-Engineered Cells.

Cardiac fibrosis poses a significant challenge in cardiovascular diseases due to its intricate pathogenesis, and there is currently no standardized and effective treatment approach. The fibrotic process entails the involvement of various cell types and molecular mechanisms, such as fibroblast activation and proliferation, increased collagen synthesis, and extracellular matrix rearrangement. Traditional therapies often fall short in efficacy or carry substantial side effects. However, recent studies have shown that Chimeric Antigen Receptor T (CAR-T) cells can selectively target and eliminate activated cardiac fibroblasts (CFs) in mice, leading to reduced cardiac fibrosis and improved myocardial tissue compliance. This breakthrough presents a new and promising avenue for treating cardiac fibrosis. Currently, CAR-T cell-based therapy for cardiac fibrosis is undergoing animal experimentation, indicating ample scope for enhancement. Future investigations could explore the application of CAR cell therapy in cardiac fibrosis treatment, including the potential of CAR-natural killer (CAR-NK) cells and CAR macrophages (CAR-M), offering novel insights and strategies for combating cardiac fibrosis.

Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations.

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.

Impact of Malnutrition on the Length of Stay for Hospitalized Chimeric Antigen Receptor T-cell (CAR-T) Therapy Patients in the United States (2020).

Background Chimeric antigen receptor T-cell (CAR-T) therapy offers a promising treatment for certain malignancies but can be associated with complications. Malnutrition and cachexia are common in cancer patients and may worsen outcomes. This study investigated the impact of malnutrition on the length of hospital stay (LOS) in patients with hematologic malignancies undergoing CAR-T therapy. The analysis focused on different subpopulations, including those with acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and non-Hodgkin lymphoma (NHL) excluding DLBCL. Methods Utilizing the 2020 National Inpatient Sample (NIS) data, we performed survey-based mean estimation analyses for LOS across various subpopulations of CAR-T therapy patients. These subpopulations were defined by specific diagnoses: ALL, myeloma, DLBCL, and NHL excluding DLBCL. We compared the LOS between patients with and without malnutrition using STATA accounting for the complex survey design. Cachexia was included as disease-induced malnutrition. Results The total CAR-T population used for analyses included 439 patients, and malnutrition was present in 50 (11.39%). The overall CAR-T population demonstrated a significantly longer LOS for patients with malnutrition (30.92 days, 95% CI: 24.30 to 37.54) compared to those without malnutrition (17.97 days, 95% CI: 15.48 to 20.46, p = 0.0002). This trend held true across subgroups. Specifically, the ALL population had a significantly longer LOS with malnutrition (45.25 days, 95% CI: 35.46 to 55.04) compared to non-malnourished patients (27.58 days, 95% CI: 16.74 to 38.42, p = 0.0279). For the DLBCL population, the mean LOS was 24.47 days (95% CI: 19.22 to 29.71) with malnutrition and 17.17 days (95% CI: 13.29 to 21.04, p = 0.0161) without malnutrition. The NHL population excluding DLBCL exhibited a mean LOS of 33.86 days (95% CI: 22.66 to 45.07) for malnourished patients and 17.44 days (95% CI: 14.76 to 20.11, p = 0.0055) for non-malnourished patients. The myeloma population showed a similar trend although not statistically significant, with a mean LOS of 39.00 days (95% CI: -3.54 to 81.54) for malnourished patients and 18.03 days (95% CI: 15.02 to 21.03, p = 0.3337) for non-malnourished patients. These findings highlight significant variations in LOS across different CAR-T-treated cancer subtypes, emphasizing the impact of malnutrition on healthcare resource utilization in oncology. Conclusion Malnutrition is associated with a significantly longer hospital stay among patients undergoing CAR-T therapy. This trend is consistent across various subpopulations, including those with ALL, DLBCL, and NHL (excluding DLBCL). While the impact of malnutrition on LOS was not statistically significant in the myeloma population, this could potentially be attributed to the smaller sample size in this group. Overall, these findings underscore the critical role of nutritional status in managing patients undergoing CAR-T therapy. Future studies should investigate the most effective methods for identifying and treating malnutrition in this patient population to reduce hospital stays and optimize overall patient care.

Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches

Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein–protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.

Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy.

Chimeric Antigen Receptor (CAR)-T-cell therapy has revolutionized cancer immune therapy. However, challenges remain including increasing efficacy, reducing adverse events and increasing accessibility. Use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology can effectively perform various functions such as precise integration, multi-gene editing, and genome-wide functional regulation. Additionally, CRISPR screening using large-scale guide RNA (gRNA) genetic perturbation provides an unbiased approach to understanding mechanisms underlying anti-cancer efficacy of CAR T-cells. Several emerging CRISPR tools with high specificity, controllability and efficiency are useful to modify CAR T-cells and identify new targets. In this review we summarize potential uses of the CRISPR system to improve results of CAR T-cells therapy including optimizing efficacy and safety and, developing universal CAR T-cells. We discuss challenges facing CRISPR gene editing and propose solutions highlighting future research directions in CAR T-cell therapy.

Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs

The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve the safety and efficacy of gene-modified T cells. Split ON- or OFF-switch CARs involve the dissociation of tumor-antigen binding from T cell activation (i.e., CD3ζ) on the receptor (R-) and signaling (S-) chains, respectively, that either associate or are disrupted in the presence of a small molecule. Here, we have developed an inducible (i)ON-CAR comprising the anti-apoptotic B cell lymphoma protein 2 protein in the ectodomain of both chains which associate in the presence of venetoclax. We showed that inducible ON (iON)-CAR T cells respond to target tumors cells in the presence of venetoclax or the BH3 mimetic navitoclax in a dose-dependent manner, while there is no impact of the drugs on equivalent second generation-CAR T cells. Within 48 h of venetoclax withdrawal, iON-CAR T cells lose the ability to respond to target tumor cells in vitro as evaluated by Interferon-gamma (IFNγ) production, and they are reliant upon the presence of venetoclax for in vivo activity. Finally, by fusing a degron sequence to the endodomain of the iON-CAR S-chain we generated an all-in-one ON/OFF-switch CAR, the iONØ-CAR, down-regulated by lenalidomide within 4 to 6 for functionally inactive T cells (no IFNγ production) within 24 h. We propose that our remote-control CAR designs can reduce toxicity in the clinic. Moreover, the periodic rest of iON and iONØ-CAR T cells may alleviate exhaustion and hence augment persistence and long-term tumor control in patients.

Therapeutic advances in hepatocellular carcinoma: an update from the 2024 ASCO annual meeting.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Recent advances in immunotherapies, targeted therapies, and combination treatments have significantly improved outcomes for many patients with HCC. This review summarizes key findings from the 2024 ASCO Annual Meeting, focusing on emerging therapies, including immune checkpoint inhibitors (ICIs), CAR-T cell therapies, oncolytic viruses, and locoregional treatments like transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). ICIs, particularly when combined with other agents, have shown promising efficacy, though challenges such as immune-related adverse events and resistance mechanisms remain. CAR-T cell therapies and oncolytic viruses offer novel therapeutic avenues for advanced HCC, but their long-term efficacy in solid tumors is still under investigation. Locoregional therapies, especially in combination with systemic treatments, continue to play a critical role in managing unresectable HCC and improving conversion rates to surgical resection. Additionally, the potential of biomarkers, such as hypoxia scores and CTNNB1 mutations, is being explored to better personalize treatment and predict patient responses. These biomarkers could pave the way for more targeted and effective therapeutic strategies. Overall, the recent studies presented at the ASCO meeting highlight progress in HCC treatment, underscoring the importance of continued innovation. Future research should focus on overcoming resistance mechanisms, optimizing combination therapies, and integrating biomarker-driven approaches to improve patient outcomes and enhance personalized treatment strategies.

Novel Immunotherapeutics for the Treatment of Non-Small Cell Lung Cancer (NSCLC) Resistant to PD-1/PD-L1 Inhibitors

Immunotherapy with PD-1/PD-L1 inhibitors is the standard method of care for the treatment of newly diagnosed advanced or metastatic NSCLC, with or without chemotherapy. Many tumors, however, develop resistance to these immunotherapy agents. There is a need to develop more effective therapies for patients with metastatic NSCLC in the second-line setting and beyond. In this review, we present an overview of novel immunotherapies being investigated regarding the treatment of these patients. We summarize completed, as well as ongoing, trials investigating these therapies as monotherapy or in combination with PD-1/PD-L1 inhibitors. These include immune co-stimulatory antibodies, T-cell agonists, oncolytic viruses, vaccines, TIL therapies, and CAR-T therapies.

Prostate Cancer, Pathophysiology and Recent Developments in Management: A Narrative Review.

Prostate cancer is the second most common cancer in men. The different stages of prostate cancer which include localised (low, intermediate, and high risk) disease, locally advanced, non-metastatic castration-resistant prostate cancer (M0 CRPCa), and metastatic disease. The main treatment of locally advanced disease is external beam radiotherapy with hormonal therapy which are associated with good prognosis. Current treatments for M0 CRPCa include androgen deprivation therapy in combination with apalutamide, darolutamide or enzalutamide, all of which are associated with good metastatic-free survival rates in clinical trials. Hormone-naive metastatic prostate cancer comprises the same treatments as M0 CRPCa, whereas further treatment includes docetaxel and abiraterone. Metastatic castration-resistant prostate cancer treatments include sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, which aim to slow down the progression of the disease and to prolong life. This article also provides insight into the development of new drugs recently approved for metastatic castration prostate cancer, which include PARP inhibitors and Lutetium-177 which have shown to have significantly good overall survival and to improve radiographic progression-free survival. In addition, new clinical trials are ongoing to test new medications such as cabozantinb and chimeric-antigen receptor T-cell therapy for the treatment of advanced prostate cancer. With the aim to slow down the progression of the disease and to prolong life, new drug developments are underway to hopefully provide a positive impact on overall survival and improve progression-free survival, especially in advanced prostate cancer.

Releasing our model T - chimeric antigen receptor (CAR) T-cells for autoimmune indications.

This review provides an update on the rapidly growing field of engineered cellular therapies for autoimmune disorders, primarily focusing on clinical experience and correlative studies with chimeric antigen receptor (CAR) T-cells. To date, two case series describing treatment with CAR T-cell therapy for systemic lupus erythematosus (SLE) suggest that drug-free remission can be sustained in patients with previously treatment-refractory disease. The outcomes of these studies are similar, despite the use of different CAR constructs and lymphodepletion regimens. Although it is not yet clear whether the patients described have truly been cured, the majority of remissions have remained durable up to last follow-up at 1-2 years from treatment. Meanwhile, mechanistic studies are providing a window into how transient B-cell depletion mediates lasting benefit. With the encouraging data in SLE, CAR T-cells and other novel B-cell-depleting agents (e.g. bispecific T-cell engagers) are now being evaluated as treatment for other autoimmune conditions, with the goal of durable response. Recent reports highlight cellular therapies as a promising strategy for patients with treatment-refractory autoimmune conditions; however, there is still limited experience, and better insight into this therapeutic approach is expected to emerge rapidly.

Distance to CAR-T Treatment Center Does Not Impede Delivery.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in relapsed or refractory large B cell lymphoma, but real-world evidence is needed to confirm safety and efficacy when facing the unique challenges of a wide geographical catchment area. We reviewed patients treated with commercially available CAR-T at a medium-sized single center in Canada (The Ottawa Hospital) between December 2020 and July 2022 (Canadian implementation started in 2020). Fifty-one patients (59% male, median age 62) traveled a median distance of 655 km (range 3-3659) for treatment. Median time from apheresis to CAR-T infusion was 36 days (range 26-81). With a median follow-up of 383 days (95% CI: 333-480), median progression-free survival (PFS) and overall survival (OS) were 257 days (95% CI: 92-NE) and 422 days (95% CI: 106-NE), respectively. The median PFS for out-of-province patients was 115 days (95% CI: 91-NE) versus 280 days for in-province patients (95% CI: 142-NE), p = 0.12. Multivariate analysis demonstrated that distance from treatment center (p = 0.05) and refractory disease status (p = 0.003) were independently associated with shorter PFS. The time from the last disease progression to CAR-T referral was longer for out-of-province patients, but there was no difference in the time of referral to CAR-T consult, apheresis, or CAR-T infusion between in-province and out-of-province patients. Our results confirm that despite the complexity of CAR-T therapy administration, Ottawa can effectively provide commercial CAR-T therapy in a timely fashion for patients from across the country.

Siltuximab for chimeric antigen receptor T-cell therapy–related CRS and ICANS: a multicenter retrospective analysis

AbstractChimeric antigen receptor T-cell (CAR-T) therapies are effective in many hematologic malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) can affect a significant number of patients. Those who develop refractory CRS or ICANS have few treatment options. Siltuximab, a monoclonal antibody binding circulating interleukin-6, has been proposed to have clinical activity in both CRS and ICANS. We conducted a multicenter retrospective analysis of siltuximab treatment for CRS and ICANS after CAR-T therapy in a real-world cohort from 6 academic centers. Fifty-four patients were evaluated. Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Of the patients with CRS at the time of siltuximab, 75% had improvement in CRS grade. Of the patients with ICANS at the time of siltuximab, 60% had improvement in ICANS grade. To our knowledge, this is the largest cohort of patients treated with siltuximab for CRS and/or ICANS after CAR-T therapies. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.