Immune Effector Cell-associated Neurotoxicity Research Articles

Efficacy and Safety of Ciltacabtagene Autoleucel in Patients With Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 Subgroup Analysis

Efficacy and Safety of Ciltacabtagene Autoleucel in Patients With Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 Subgroup Analysis

Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia Relapsed Post-HSCT

IntroductionAllogeneic Chimeric Antigen Receptor (CAR) T cells engineered with non-viral methods offer a modality to reduce costs and logistical complexity of the viral process and allow lymphodepleted patients to access CAR T cell treatment. We recently proposed the use of Sleeping Beauty (SB) transposon to engineer donor-derived T cells differentiated according to the cytokine-induced killer (CIK) cell protocol (Magnani CF et al. J Clin Invest. 2021). We report here outcomes on B-cell acute lymphoblastic leukemia (B-ALL) patients, relapsing after transplantation, treated with donor-derived anti-CD19 CAR T cells (CARCIK-CD19).MethodsWe conducted an academic, multi-center, phase I/II dose-escalation trial in patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). The infusion product was manufactured in-house starting from 50 mL of peripheral blood from the HSCT donor by electroporation with GMP-grade plasmids. All patients underwent lymphodepletion with Fludarabine (30 mg/m 2/day x 4 days) and Cyclophosphamide (500 mg/m 2/day x 2 days), before proceeding to CARCIK-CD19 infusion. We used the Bayesian Optimal Interval (BOIN) design to define a four-dose escalation scheme. Primary objectives were to define the Maximum Tolerated Dose (MTD), safety, and feasibility. Secondary objectives included the assessment of complete hematologic response (CR), duration of response (DOR), progression-free (PFS), event-free (EFS), and overall survival (OS). This study was registered at ClinicalTrials.gov, NCT03389035.ResultsFrom January 2018 to June 2021, a total of 32 patients were screened, 26 enrolled (6 children and 20 adults) and 21 infused (4 children and 17 adults). Reasons for not receiving infusion included consent withdrawal (N=1), disease progression not controlled by bridging therapy (N=3), acquisition of myeloid phenotype (N=1). The median number of prior therapies was 4 (range, 1-7) with a median time interval from HSCT to relapse of 9 months. The median BM blasts was 60% (range, 5-100%) at enrollment and 7% (range, 0-96%) post lymphodepletion. Of the 21 patients infused, CARCIK-CD19 were obtained by HLA-identical sibling (n=6, 29%), matched unrelated (n= 7, 33%), and haploidentical donors (n=8, 38%). Three patients (14%) received the first dose level of 1x10 6 CARCIK-CD19 cells/Kg, three (14%) the second of 3x10 6, and three (14%) the third of 7.5x10 6 whereas 12 patients (57%) received the fourth and last planned dose level of 15x10 6 cells/Kg, as no dose limiting toxicity (DLT) was observed. CRS was observed in six patients (three grade I and three grade II) and immune effector cell-associated neurotoxicity in two patients at the highest dose. Although 9 out of 21 had experienced acute or chronic graft-versus-host disease (GvHD) after the previous HSCT, secondary GvHD was never induced by CARCIK-CD19. Complete response was achieved by 13 out of 21 patients (61.9%, 95%CI=38-82%) and by 11 out of 15 patients treated with the 2 highest doses (73.3%, 95%CI=45-92%). Eleven of these responders were MRD-negative. Notably, the type of donor did not influence the achievement of CR 28 days post-infusion. At a median follow up of 21.6 months (range, 1.0-38.4 months), 10 patients (47.6%) are alive in CR (9 in the 2 highest dose levels). Overall, the median OS and EFS were 9.7 and 3.2 months, respectively, with a median DOR of 4.0 months (range, 1.0-23.5 months). Patients in CR at 28-days had a 6-months relapse-free survival of 48.4% (SE=14.9). EFS at 6 months was 26.5% (SE=9.9) and OS was 67.6% (SE=11.1). Among the 13 patients who achieved CR, two children underwent consolidation with a second allo-HSCT in complete remission. Adult patients did not receive any additional anti-leukemic therapies unless a relapse occurred, and four of them remained in remission and alive (+24, +9, +6, and +4 months). Robust CARCIK-CD19 cell expansion was achieved in most patients and CARCIK-CD19 cells were measurable for up to 22 months.ConclusionsSB-engineered CAR T cells induce sustained responses in B-ALL patients relapsed after HSCT irrespective of the donor type and without severe toxicities. DisclosuresLussana: Incyte: Honoraria; Pfizer: Honoraria; Astellas Pharma: Honoraria; Amgen: Honoraria. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. Biondi: Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Amgen: Honoraria; Colmmune: Honoraria.

Updated Results from CARTITUDE-1: Phase 1b/2Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Patients With Relapsed/Refractory Multiple Myeloma

Updated Results from CARTITUDE-1: Phase 1b/2Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Patients With Relapsed/Refractory Multiple Myeloma

CAR T-Cell Therapy: An Update for Radiologists.

Chimeric antigen receptor-engineered (CAR) T-cell therapy is a promising novel immunotherapy that has the potential to revolutionize cancer treatment. Four CAR T-cell therapies have received FDA approval within the last 5 years, and the role of CAR T cells is anticipated to continue to evolve and expand. However, various aspects of CAR T-cell therapies remain poorly understood, and the therapies are associated with severe side effects, including cytokine release syndrome and immune effector cell-associated neurotoxicity, which require prompt diagnosis and intervention. The purposes of this review are to describe the role of imaging in diagnosing and monitoring toxicities from CAR T-cell therapies and explore the use of various imaging techniques, including PET/CT with novel radiotracers, to predict and assess treatment response and adverse effects. It is important for radiologists to recognize the imaging findings associated with each syndrome and to recognize the typical and atypical treatment response patterns associated with CAR T-cell therapy. Given the expected increase in use of CAR T cells in the near future, radiologists should familiarize themselves with the imaging findings encountered in these novel therapies so that they can provide comprehensive and up-to-date guidance for clinical management.

Promising tolerability and efficacy results from dose-escalation in an ongoing phase Ib/II study of mosunetuzumab (M) with polatuzumab vedotin (Pola) in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin’s lymphoma (B-NHL).

7520 Background: Mosunetuzumab (M), a full-length, humanized, IgG1 bispecific antibody targeting CD20 and CD3, has shown promising efficacy and safety as monotherapy for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). The combination of M with the anti-CD79b antibody-drug conjugate, Pola, showed synergistic anti-lymphoma activity in a mouse xenograft model. These data supported a Phase Ib/II, open-label, multicenter trial of M-Pola for R/R B-NHL (GO40516, NCT03671018). Here we present early clinical data from the Phase Ib cohort. Methods: Pts with R/R follicular lymphoma (FL, grade [Gr] 1–3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL) and FL Gr 3b (FL3b), received Cycle (C) 1 step-up doses of M on Day (D) 1 (1mg) and D8 (2mg), the target dose on C1D15, then continued at the target dose on C2D1 onwards. M was given every 21 days for eight cycles (or 17 cycles if stable disease or a partial response after C8). Pola (1.8mg/kg) was given with M on D1 of each cycle for six cycles. Results: As of November 17, 2020, 22 pts had received M-Pola (M target doses: 9mg, n=7; 20mg, n=3; 40mg, n=6; 60mg [with D1 dose of 30mg from C3 onwards], n=6). Pts had DLBCL (n=12), FL (n=3), FL3b (n=3) and trFL (n=4). Pt characteristics include: median age of 70 (38–81) years; median of 3 (1–10) prior lines of therapy; 7 (32%) pts had prior CAR-T therapy; 17 (77%) and 19 (86%) pts had disease refractory to last prior therapy and prior anti-CD20 therapy, respectively. Median follow-up duration was 9.6 (0.7–23.7) months. The most frequent treatment-related adverse events (AEs) were neutropenia (45.4%), fatigue, nausea and diarrhea (all 36.4%). Cytokine release syndrome (CRS) was observed in 2 pts (9.1%; both Gr 1 by ASTCT 2019 criteria). One dose-limiting toxicity (Gr 3 new onset atrial fibrillation) was observed in the 40mg cohort. The maximum tolerated dose was not exceeded. The most common Gr ≥3 and serious AEs were both neutropenia, observed in 8 (36.4%) and 3 (13.6%) pts, respectively. Two (9.3%) Gr 5 AEs occurred: sudden cardiac death (n=1) and respiratory failure (n=1); neither was deemed treatment related. No immune effector cell-associated neurotoxicity was observed. The Table shows preliminary efficacy data. Preliminary efficacy in the dose-escalation cohort. Conclusions: These data indicate that M-Pola has an acceptable safety profile, with no Gr ≥2 CRS observed, and promising efficacy in pts with R/R NHL with predominantly aggressive disease. The Phase II expansion cohort in R/R DLBCL is ongoing, with no mandatory hospitalization required. Clinical trial information: NCT03671018. [Table: see text]

Therapeutic Strategies for Targeting IL-1 in Cancer.

Simple SummaryInterleukin-1 cytokines are key proinflammatory cytokines which have been implicated with differing pro- and antitumorigenic properties. Recent years have brought exciting insights and developments in IL-1-targeted therapies. Here, we present an overview of past and present research focusing on the role of IL-1 in cancer, with a special focus on clinical research and on therapeutic implications. With this, we strive to assist scientists in their future research objectives and to highlight possible directions for IL-1-targeting therapies in the coming years.Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several clinical trials have been conducted, shedding light on the role of IL-1 blocking agents for the treatment of cancer. Additionally, recent developments in the field of immuno-oncology have implicated IL-1-induced signaling cascades as a major driver of severe chimeric antigen receptor T cell-associated toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity. In this review, we summarize current clinical trials investigating the role of IL-1 blockade in cancer treatment and elaborate the proposed mechanism of these innovative treatment approaches. Additionally, we highlight cutting-edge developments utilizing IL-1 blocking agents to enhance the safety and efficacy of adoptive T cell therapy.

Neurologic Toxicities of Immunotherapy.

Immunotherapy has revolutionized treatment of cancer over the past two decades. The antitumor effects of immunotherapy approaches are at the expense of growing spectrum of immune-related adverse events (irAEs) due to cross-reactivity between the tumor and normal host tissue. These adverse events can happen in any organ and range from mild to severe and even life-threatening conditions. While neurological irAEs associated with immune checkpoint inhibitors (CPIs) are rare, they pose a significant challenge in management as the clinical phenotypes are heterogenous and frequently necessitate cessation of therapy and systemic immune suppression and lead to transient functional decline. On the other hand, immune effector cell-associated neurotoxicity (ICANS) is common, frequently occurs in conjunction with cytokine release syndrome (CRS), and poses a significant clinical challenge to the development and widespread use of these effective therapies. Early recognition of these neurological syndromes, timely diagnosis, and thoughtful management are key for further clinical development of these effective therapies in cancer patients. Here, we describe clinical phenotypes of CPI-induced neurological complications and ICANS and discuss steps in clinical monitoring, diagnosis, and effective management.

Chimeric Antigen Receptor, Teamwork, Education, Assessment, and Management (CAR-TEAM): A Simulation-Based Inter-professional Education (IPE) Intervention for Management of CAR Toxicities.

Chimeric antigen receptor (CAR) therapies such as tisagenlecleucel, indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukemia (ALL), have been associated with striking treatment outcomes and overall survival. Yet, they are also associated with unique and potentially life-threatening complications. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are generally reversible complications of CAR therapies, but many patients may require critical care support especially if they are not promptly recognized and appropriately managed by frontline healthcare staff. As CAR therapies become more widely available, it is important that inter-professional staff members be aware of general principles regarding diagnosis and management. We hypothesized that an inter-professional education (IPE) simulation-based education intervention (CAR-TEAM) would improve knowledge base and confidence regarding complications of CAR therapies among inter-professional staff. Here, we demonstrate that following CAR-TEAM training, >90% of participants demonstrated knowledge proficiency and confidence in the IPE content area. CAR-TEAM training may serve as an important tool to establish initial and continued competency among sites introducing CAR therapies.

Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.

Management of CAR T-Cell Toxicities: Concordance and Divergence between Healthcare Providers and Expert Consensus Recommendations

Background: Chimeric antigen receptor (CAR) T-cell therapy has been a major innovative breakthrough for hematologic malignancies with 2 currently FDA approved CAR T-cell products (tisagenlecleucel and axicabtagene ciloleucel) and several others in different stages of clinical investigation. However, these therapies are associated with unique safety profiles and potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), that require vigilant monitoring and prompt recognition and management to ensure patient safety and optimal therapeutic benefit. We developed an online interactive decision support tool at www.clinicaloptions.com/carttool to give healthcare providers (HCPs) case-specific, evidence-based guidance from experts on the management of adverse events (AEs) due to CAR T-cell therapy. Here, we report a comparison of CAR T-cell toxicity management among HCPs using the tool vs the expert consensus recommendations in the tool. Methods: In March 2019, a panel of 5 experts provided consensus guidance for the screening, prophylaxis, monitoring, and management of CRS and ICANS in patients for which CAR T-cell therapy was either planned or started. This information was used to build the interactive online tool. To use the online tool, HCPs enter the AE that the patient is experiencing, either CRS or ICANS; the grade or severity of the event, per the American Society for Transplantation and Cellular Therapy consensus grading for CRS and ICANS (Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638); and their planned management approach. The HCPs were then shown the expert management recommendation for that specific AE scenario. After viewing the expert management recommendation, HCPs were asked if it impacted their intended management approach. Results: Between May and July 2019, 115 HCPs entered 166 unique case scenarios into the tool. The majority of cases (58%) entered were for patients who were planned for CAR T-cell therapy or who had started therapy without yet experiencing an AE, for which users received expert recommendations on pretreatment screening along with AE prophylaxis and monitoring. Of the 69 cases entered for patients who had received CAR T-cell therapy and were experiencing an AE, 71% were CRS and 29% were neurotoxicity/ICANS. The majority of CRS cases (67%) were intermediate grade (2/3) whereas the ICANS cases were evenly distributed across all grades (1-4). Overall the planned toxicity management strategy of HCPs matched the expert recommendations in 45% of cases, with the greatest discordance for CRS management, where the rate of agreement was 37% (Figure). The proportion of cases in which the planned management strategies of HCPs matched expert recommendations also varied by syndrome grade/severity between US and non-US HCPs. There was no concordance (0%) among US HCPs compared with non-US HCPs (60%) for grade 1 AEs, whereas greater concordance was found in the management of grade 2 and grade 3 AEs among US HCPs (67% and 57%, respectively) compared with non-US HCPs (43% and 44%, respectively; Figure). Of the 15 grade 1 AEs entered by users, only 5 came from US HCPs. Among the 48% of HCPs who answered the optional survey on the impact of the tool on their intended management plan, 48% indicated that the expert recommendations changed their approach, and 80% reported practicing at a treatment center authorized to administer CAR T-cell therapy. Conclusions: These data suggest that many HCPs are challenged to optimally manage toxicities related to CAR T-cell therapy and are not managing their patients in concordance with expert recommendations. Use of an online tool providing easy access to evidence-based consensus expert recommendations may improve patient care and safety in patients treated with CAR T-cell therapy. A detailed analysis of the tool, including case entries and planned management vs expert consensus recommendations for each toxicity and grade, will be presented. Figure. Planned Management of HCPs Compared With Expert Recommendations Figure Disclosures Frigault: Novartis: Patents & Royalties: Royalty; Arcellx, Celgene, Foundation Medicine, Kite/Gilead, Nkarta, Novartis, and Xenetic: Consultancy. DeAngelo:GlycoMimetics: Research Funding; Abbvie: Research Funding; Blue Print Medicines: Consultancy, Research Funding; Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Shire: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy. Galinsky:Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: Member on specialty oncology board; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Paul:Agios: Consultancy; Pfizer: Consultancy. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy.