PET/CT in the Evaluation of CAR-T Cell Immunotherapy in Hematological Malignancies.

Chimeric antigen receptor (CAR)-T cell-based immunotherapy has emerged as a path-breaking strategy for certain hematological malignancies. Assessment of the response to CAR-T therapy using quantitative imaging techniques such as positron emission tomography/computed tomography (PET/CT) has been broadly investigated. However, the definitive role of PET/CT in CAR-T therapy remains to be established. [18F]FDG PET/CT has demonstrated high sensitivity and specificity for differentiating patients with a partial and complete response after CAR-T therapy in lymphoma. The early therapeutic response and immune-related adverse effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome can also be detected on [18F]FDG PET images. In otherwise asymptomatic lymphoma patients with partial response following CAR-T therapy, the only positive findings could be abnormal PET/CT results. In multiple myeloma, a negative [18F]FDG PET/CT after receiving B-cell maturation antigen-directed CAR-T therapy has been associated with a favorable prognosis. In leukemia, [18F]FDG PET/CT can detect extramedullary metastases and treatment responses after therapy. Hence, PET/CT is a valuable imaging tool for patients undergoing CAR-T therapy for pretreatment evaluation, monitoring treatment response, assessing safety, and guiding therapeutic strategies. Developing guidelines with standardized cutoff values for various PET parameters and tumor cell-specific tracers may improve the efficacy and safety of CAR-T therapy.

Charting the Course: Sequencing Immunotherapy for Multiple Myeloma.

Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell-directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.

Advances in CAR-T-cell therapy in T-cell malignancies.

Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.

Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy.

BACKGROUND: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern. METHODS: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. RESULTS: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. CONCLUSIONS: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy.

Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy for treatment of myeloma. Targeted messenger RNA sequencing revealed the presence of CAR gene product in tumor cells. Whole-genome sequencing of samples of tumor and peripheral blood identified a single lentiviral insertion site within the second intron of the SSU72 gene. In addition, numerous genetic alterations that may have contributed to malignant transformation were identified in the tumor sample. (Funded by MedStar Georgetown University Hospital.).

Recent Advances in CAR-T Therapy.

Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a patient's T cells are programmed to act against tumor cells. We discuss the process of manufacturing CAR-T cells, the common side effects of therapy, and the recent emerging risk of T-cell malignancies after treatment.

Anti-BCMA CAR-T cell-based therapies and bispecific antibodies in the immunotherapy era: are we ready for this?

INTRODUCTION: Therapeutic strategies against multiple myeloma (MM) have evolved dramatically in recent decades, with unprecedent results in the treatment landscape, culminating in the recent incorporation of novel agents in the anti-myeloma armamentarium. AREAS COVERED: BCMA represents one of the most promising targets in MM and currently available immune approaches, either approved or under active investigation, are clearly showing their greater potential over standard regimens. In this context, immunotherapies based on chimeric antigen receptor (CAR)-engineered T-cells and bispecific antibodies (BsAbs) have taken center stage, being the ones that are yielding the most promising results in clinical trials. This review focuses on the current landscape of BsAbs and CAR-T, summarizing the latest advances and possible future developments. EXPERT OPINION: CAR-T and BsAbs anti-BCMA strategies represent breakthrough therapies against MM. However, their inclusion in clinical practice is almost feared, due to the associated limitations, some of which have been addressed here. Meanwhile, all the efforts should be focused on individualizing and choosing the most suitable candidates for each treatment and to understand how to combine, or sequence, these therapies to improve efficacy and minimize toxicity, especially for those patients with limited available treatment options.

Current understanding and management of CAR T cell-associated toxicities.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. As CAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities.

Role of radiation in chimeric antigen receptor T-cell therapy for patients with relapsed/refractory non-Hodgkin lymphoma: Current studies and future prospects.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment approach for patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). However, the long-term prognosis has been discouraging. Moreover, the urgent resolution of two critical issues is necessary: minimize tumor burden before CAR-T infusion and control fatal toxicities post CAR-T therapy. By combining radiotherapy (RT), the safety and efficacy of CAR-T can be improved. RT can serve as bridging therapy, reducing the tumor burden before CAR-T infusion, thus enabling safe and successful CAR-T infusion, and as salvage therapy in cases of CAR-T therapy failure. This review aims to discuss the current evidence supporting the use of RT in CAR-T therapy for patients with R/R NHL. Although most studies have shown a positive role of RT in combined modality treatments for patients undergoing CAR-T therapy, the synergy gained from these remains uncertain. Furthermore, the optimal dose/fraction and radiation response require further investigation.

Rapid response in relapsed follicular lymphoma to novel anti-CD19 CAR-T therapy with pseudo-progression and cytomegalovirus infection: A case report.

CD19-directed chimeric antigen receptor (CAR) T cell therapy has been shown to achieve a considerably durable response in patients with refractory or relapsed B cell non-Hodgkin lymphomas. Most of these CARs were generated by lentivirus. With the exception of Yescarta and Tecartus, few patients with relapsed-/refractory- lymphoma have been treated clinically with a CARs using retroviral vector (RV). Here, we reported a relapsed/refractory grade 2 follicular lymphoma patient with multiple chemotherapy failures, and was treated with a novel CD19 CAR-T cell manufactured from a RV. After tumor burden was reduced with Obinutuzumab and Duvelisib, the patient was infused novel CD19 CAR-T cells at a dose of 3 × 106 cells/ kg. Then he experienced a rapid response and achieved almost complete remission by day 26. Only grade 2 CRS, bilateral submaxillary lymph node enlargement and cytomegalovirus (CMV) infection occurred without neurotoxicity, and the patient's condition improved after a series of symptomatic treatments. In addition, CAR copy number peaked at 532,350 copies/µg on day 15 and continued to expand for 5 months. This may be the first case report of RV preparation of novel CD19 CAR-T cells for direct treatment of recurrent follicular lymphoma. We will observe its long-term efficacy and conduct trials in more patients in the future.

Economic evaluation of anti-CD19 CAR T-cell pathway for large B-cell lymphomas in the real-life setting: the experience of an Italian hub center in the first three years of activity.

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30 days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy.

Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy.

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

Chimeric Antigen Receptor T-Cell Access in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Association of Access with Social Determinants of Health and Travel Time to Treatment Centers.

Large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma. Chimeric antigen receptor T-cell (CAR T) therapy represents a novel treatment with curative potential for relapsed or refractory (R/R) LBCL, but there are access barriers to this innovative therapy that are not well-studied. Study objectives were: (1) Assess the impact of geographic factors and social determinants of health (SDOH) on access to treatment with CAR T in a sample of patients with R/R LBCL and ≥2 prior lines of therapy (LOT). (2) Compare and contrast patient characteristics, SDOH, and travel time between patients with R/R LBCL who received CAR T and those who did not. An observational, nested case-control study of patients with R/R LBCL, ≥2 prior LOT, not in a clinical trial, identified using 100% Medicare Fee-For-Service and national multi-payer claims databases. Patients were linked to near-neighborhood SDOH using 9-digit ZIP-code address. Driving distance and time between residence and nearest CAR T treatment center (TC) was calculated. Patients were stratified based on treatments received upon third LOT initiation (Index Date) or later: (1) received CAR T and (2) did not receive CAR T. Multivariable logistic regression was used to evaluate factors associated with CAR T. 5011 patients met inclusion criteria, with 628 (12.5%) in the CAR T group. Regression models found the likelihood of receiving CAR T decreased with patient age (odds ratio [OR] = .96, P < .001), and males were 29% more likely to receive CAR T (OR = 1.29, P = .02). Likelihood of CAR T increased with Charlson Comorbidity Index (CCI; OR = 1.07, P < .001) indicating patients with more comorbidities were more likely to receive CAR T. Black patients were less than half as likely to receive CAR T than White patients (OR = .44, P = .01). Asian patients did not significantly differ from White patients (OR = 1.43, P = .24), and there was a trend for Hispanic patients to have a slightly lower likelihood of CAR T (OR = .50, P = .07). Higher household income was associated with receipt of CAR T, with the lowest income group more than 50% less likely to receive CAR T than the highest (OR = .44, P = .002), and the second lowest income group more than 30% less likely (OR = .68, P = .02). Finally, likelihood of CAR T therapy was reduced when the driving time to the nearest TC was 121 to 240 minutes (reference group: ≤30 minutes; OR = .64, P = .04). Travel times between 31 and 121 or greater than 240 minutes were not significantly different from ≤30 minutes. Payer type was collinear with age and could not be included in the regression analysis, but patients with commercial insurance were 1.5 to 3 times more likely to receive CAR T than other payers on an unadjusted basis. We identified significant disparities in access to CAR T related to demographics and SDOH. Patients who were older, female, low income, or Black were less likely to receive CAR T. The positive association of CCI with CAR T requires further research. Given the promising outcomes of CAR T, there is urgent need to address identified disparities and increase efforts to overcome access barriers.

Off-the-shelf CAR-T cell therapies for relapsed or refractory B-cell malignancies: latest update from ASH 2023 annual meeting.

Currently, many off-the-shelf chimeric antigen receptor (CAR)-T cell products are under investigation for the treatment of relapsed or refractory (R/R) B-cell neoplasms. Compared with autologous CAR-T cell therapy, off-the-shelf universal CAR-T cell therapies have many potential benefits, such as immediate accessibility for patients, stable quality due to industrialized manufacturing and additional infusions of CAR-T cells with different targets. However, critical challenges, including graft-versus-host disease and CAR-T cell elimination by the host immune system, still require extensive research. The most common technological approaches involve modifying healthy donor T cells via gene editing technology and altering different types of T cells. This article summarizes some of the latest data from preclinical and clinical studies of off-the-shelf CAR-T cell therapies in the treatment of R/R B-cell malignancies from the 2023 ASH Annual Meeting (ASH 2023).

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China.

BACKGROUND: Relapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready process developed in China, demonstrated remarkable efficacy and manageable safety in the pivotal RELIANCE study. However, no published data are available on the "real-world" use of relma-cel, especially for patients with CNS involvement. PATIENTS AND METHODS: Retrospective analyses were conducted for commercial relma-cel used in patients with R/R CNSL at 12 clinics. The primary endpoint was to evaluate the proportion of patients who achieved complete response (CR) at 3 months. Secondary endpoints included best complete response (BCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the incidence of adverse events. RESULTS: Among the 22 CNSL patients (12 primary CNSLs; 10 secondary CNSLs), the best overall response rate was 90.9% and the BCR rate was 68.2%. With median follow-up of 316 days (range, 55-618 days), the estimated 1-year PFS rate, DOR, and OS rate were 64.4%, 71.5%, and 79.2%, respectively. Significant clinical benefits were observed in patients who were in durable CR or partial response to the most recent prior therapy preleukapheresis and received relma-cel as consolidation therapy (n=8), with 1-year PFS rate of 100.0% versus 41.7% (p=0.02). In addition, in terms of primary endpoint, non-CR at 3 months postinfusion seemed to be predictive of a worse prognosis, with an estimated 1-year PFS of 83.3% versus 37.0% (p=0.03), respectively. CRS occurred in 72.9% of patients (grade 3: 4.5%) and immune effector cell-associated neurotoxicity syndrome in 36.4% of patients (grade 3: 4.5%). With the add-on agent PD-1 inhibitor (tislelizumab) to the ongoing BTKi, significant re-expansions of CAR T-cell were detected by quantitative PCR or flow cytometry after a median of 2 weeks (range, 12-32 days). CONCLUSIONS: This study was the first and largest real-world study of commercial relma-cel for R/R CNSL, demonstrating promising efficacy and acceptable safety. We reaffirmed the benefit of immuno-agents such as BTKi or PD-1 inhibitor on CAR T-cell re-expansion and hypothesized a dual-agent CAR-T related combinatorial therapies, which warrants further validation. Most importantly, we highlighted the earlier use of CAR T-cell therapy as a consolidative therapy for patients sensitive to salvage therapy, which provided an impetus and inspired-future strategy.