Decentralized or point-of-care (POC) manufacture of CAR-T cells is a potential strategy to improve accessibility and reduce cost and logistic challenges. A total of 10 relapsed/refractory patients (B cell acute lymphoblastic leukemia [B-ALL] N = 6, diffuse large B cell lymphoma [DLBCL] N = 4) were enrolled in this POC phase 1 study. Chimeric antigen receptor (CAR)-T cells were manufactured using the fully automated CliniMACS Prodigy system. The CAR-T cell products had a median 15-fold expansion with a median transduction rate of 38%. The immunophenotypic characterization indicates a significant increase in central memory and effector T cells. All the patients were infused with fresh CAR-T cells. Complete remission rates were 100% for B-ALL and 50% for DLBCL. At a median follow-up of 15 months, 8 of 10 patients remain without disease progression. Adverse events reported were cytokine release syndrome grade 2 or higher in 2 of 10 patients. None of the patients developed immune effector cell-associated neurotoxicity syndrome. Late hematological toxicity of grade 2 or higher was noted only in one patient. Evaluation of health care resource utilization demonstrates that the median cost was US$12,724, while the manufacturing cost was US$35,107. Our data highlight the safety, efficacy, low cost, and potential to enhance the accessibility of CAR-T cell therapy in low- and middle-income countries through a fully automated and closed manufacturing platform.

Tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel) are approved CD19 chimeric antigen receptor T-cell therapy (CAR T) products for young adults (YA) with relapsed/refractory B-cell acute lymphoblastic leukemia. A distinct analysis of YAs receiving commercial CD19 CAR T has not been reported. Using retrospective data from the Pediatric Real-World CAR T Consortium and the Real-World Outcomes of CAR T in Adult ALL collaboration, we describe the efficacy and safety of tisa-cel and brexu-cel in 70 YAs (18-26 years; tisa-cel, n = 50; brexu-cel, n = 20). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed more frequently for brexu-cel vs tisa-cel (CRS, 85% vs 56%; ICANS, 40% vs 18%). Complete response rates were similar between products at 80% for brexu-cel and 88% for tisa-cel. Relapse-free survival (RFS) at 12 months was 46% for brexu-cel and 36% for tisa-cel. Durability of remission over 12 months was 61% for brexu-cel vs 41% for tisa-cel; 12-month overall survival (OS) for brexu-cel was 84% vs 68% for tisa-cel. In multivariate analysis, low disease burden was associated with improved OS, whereas inotuzumab before CAR T was associated with inferior outcomes. This study demonstrates comparable real-world efficacy among YAs receiving CD19 CAR T irrespective of CAR T construct; however, rates of toxicity seem higher with brexu-cel.

Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Engraftment syndrome (ES) is a non-infectious febrile complication of hematopoietic cell transplantation (HCT), with diagnostic challenges, particularly in the allogeneic setting. The increasing use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis highlights the need for a re-examination of ES in this contemporary context.

To evaluate the incidence and clinical presentation of engraftment syndrome (ES), as well as its impact on transplant outcomes in the era of PTCy-based prophylaxis.

We retrospectively analyzed 552 allogeneic HCT patients receiving PTCy, sirolimus, and mycophenolate mofetil across various donor types. To improve ES diagnosis in this setting, we proposed new criteria in which peri-engraftment fevers (PEFs) (day -4 to day +3 before and after myeloid engraftment) were classified as follows: definite ES (PEF meeting Spitzer, Maiolino, or Grant criteria); probable ES (PEF plus ≥1 additional ES sign); and possible ES (PEF without additional signs).

Among the 80 patients (14.5%) who developed PEF, 24 (30%) fulfilled criteria for definite engraftment syndrome (ES), 14 (17.5%) for probable ES, and 42 (52.5%) for possible ES. The 30-day cumulative incidence of overall ES was 15% (95% CI, 12-18), comprising 4.4% (95% CI, 2.9-6.4) for definite ES, 2.6% (95% CI, 1.5-4.2) for probable ES, and 7.8% (95% CI, 5.7-10) for possible ES. In addition to fever, the most frequently observed ES-related symptoms included diarrhea (n = 18), weight gain (n = 14), skin rash (n = 11), hepatic dysfunction (n = 8), and pulmonary infiltrates (n = 7). Risk factors associated with the development of ES were younger age (defined as <40 years), underlying lymphoproliferative neoplasms, haploidentical donor transplantation, and a history of prior cytokine release syndrome. Importantly, ES resolved within 48 hours in 75 of the 80 cases (94%), and no deaths were attributed to PEF or ES episodes. Interestingly, the presence of ES was significantly associated with improved overall survival and event-free survival, potentially reflecting a composite effect of trends toward lower relapse rates and reduced non-relapse mortality in affected patients.

ES in PTCy-based allogeneic HCT is frequent but rarely meets traditional criteria, highlighting the potential value of a refined three-category classification. Our findings suggest an unexpected survival benefit, possibly linked to the immunomodulatory effects of PTCy, and underscore the need for further studies to validate this classification and investigate the underlying biological mechanisms.

Chimeric antigen receptor T-cell (CAR-T) therapy for hematological malignancies causes a neurological complication known as immune effector cell-associated neurotoxicity syndrome (ICANS). The precise neurocognitive pathology underlying ICANS remains incompletely described. The aim of this study is to elucidate that persistent cognitive dysfunction as potential neurotoxicity of CAR-T therapy.

This was a single-center consecutive study of ICANS caused by CAR-T therapy for B-cell acute lymphoblastic leukemia. We determined the cognitive functions of all patients with ICANS at the onset of ICANS symptoms and followed them up in the neurology department thereafter.

Among the 10 CAR-T cases between 2020 and 2022, three patients had ICANS. None of the patients experienced seizures. Of the three patients, the preadolescent patient showed decreased levels of consciousness, tremors, and striatal signs without cognitive dysfunction. The other two adolescent and young adult patients presented with cognitive decline, short- and long-term memory loss, and emotional disturbances. Although the Immune Effector Cell-Associated Encephalopathy score remained low, the cognitive impairment was profound and disabling in both cases. The neurological status of all patients fully recovered to pre-CAR-T status within one month.

The findings in our cases indicate that persistent cognitive dysfunction may be a potentially under-recognized outcome of neurotoxicity due to CAR-T therapy for B-cell acute lymphoblastic leukemia in adolescents and young adults. Detailed neuropsychologic assessments may be beneficial for CAR-T therapy.

The aim of this study was to evaluate the value of 18 F-FDG PET/CT in predicting outcomes and toxicity for patients with B-cell non-Hodgkin lymphoma (B-NHL) who underwent chimeric antigen receptor T (CAR-T) cell therapy.

This retrospective study included B-NHL patients who underwent CAR-T therapy and had pre-infusion 18 F-FDG PET/CT images. We recorded SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and various clinical and laboratory indexes. The primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using the Kaplan-Meier method. In addition, we reported the correlation between PET/CT parameters and the objective response (OR), as well as cytokine release syndrome (CRS).

A total of 133 patients were enrolled in this study. The median follow-up duration was 20.8 months. SUVmax (with a cutoff value of 15.65) emerged as an independent metabolic parameter associated with PFS, OS, and OR. Patients with SUVmax ≥15.65 had a median PFS of 9.13 months (95% CI: 0.11-18.16), while the PFS for those with SUVmax<15.65 was not reached ( P =0.006). Furthermore, patients with SUVmax ≥15.65 exhibited significantly shorter average OS compared with those with SUVmax<15.65 (26.89 mo vs. 45.14 mo, P =0.010). In addition, the odds ratio for achieving an OR in patients with SUVmax ≥15.65 was found to be lower at 0.173 (95% CI: 0.056-0.539). Other factors associated with PFS included ECOG-PS, B symptoms, bulky mass, and extranodal sites, whereas IPI and LDH were associated with OS. Furthermore, SUVmax and Deauville scores showed a weak positive correlation with the occurrence of CRS.

The pretreatment PET/CT parameter SUVmax appears to be a promising predictive factor for efficacy and prognosis, as well as being associated with the occurrence of CRS. Consequently, we can conclude that this metabolic parameter from pretreatment PET/CT scans may serve as a valuable tool in guiding patient selection for CAR-T therapy and predicting potential side effects.

Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory syndrome triggered by infections, malignancies, or rheumatologic conditions. Effective management requires identifying and treating the acute trigger while addressing underlying factors and calming the inflammatory response. Like sepsis, sHLH represents a cytokine storm resulting from diverse triggering events rather than a standalone diagnosis. This review synthesizes current literature and the authors' clinical experience to provide a comprehensive framework for diagnosing and managing sHLH, emphasizing the importance of tailored, trigger-specific interventions. Emerging diagnostic tools and therapeutic strategies and improved mechanistic understanding of sHLH hold promise for improving outcomes in this challenging condition.

Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a complication of adoptive cell therapy. Presenting with clinical manifestations of hyperinflammation and surrogate indicators of hyperinflammation such as elevations in serum ferritin and hepatic transaminases, decreasing cell counts, and hypofibrinogenemia, IEC-HS resembles primary and other forms of secondary hemophagocytic lymphohistiocytosis. Nonetheless, this is an iatrogenic complication resulting from the induction of hyperinflammatory pathways during T-cell-mediated anticancer targeting. Distinct from cytokine release syndrome, IEC-associated neurotoxicity syndrome, and IEC-associated hematotoxicity, IEC-HS can be life-threatening. Identification of IEC-HS, optimization of treatment strategies, and use of supportive care are critical to improving outcomes.

Anti-CD19 CAR-T therapy has been a breakthrough in treatment of primary refractory or relapsed large B-cell lymphoma (r/r LBCL) and is poised to supplant previous second line of high dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). However, in clinical practice, high risk patients with chemoimmunotherapy sensitive disease continue to receive salvage chemoimmunotherapy or cannot access CAR-T in a timely manner and thus may still proceed to HDT/ASCT. Little is known about clinical outcomes of CAR-T in patients who receive HDT/ASCT compared to those who are transplant-naïve.

We conducted a retrospective study of patients with r/r LBCL who previously underwent HDT/ASCT or were transplant-naïve (n = 97) and received axicabtagene ciloleucel after at least 2 prior therapy lines between 1/1/2018 to 12/31/2021. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse/progression.

82 (84.5%) patients were transplant-naïve and 15 (15.5%) previously received HDT/ASCT. No differences were found in the incidence of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, length of hospital admission, or incidence of cytopenia at day 30. 90-day response, PFS, OS, cumulative incidence of relapse/progression, and NRM were not different. Factors that adversely affected outcomes were prior bridging therapy, elevated LDH or thrombocytopenia at time of lymphodepleting chemotherapy, and worse ECOG performance status.

Prior treatment with HDT/ASCT does not compromise the safety and efficacy of anti-CD19 CAR-T therapy, suggesting a continued role for HDT/ASCT in treatment of select patients with r/r DLBCL.

Diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) is the most common aggressive lymphoma and can be cured with CHOP-R immunochemotherapy in 60% of cases. The second-line therapy includes salvage regimens followed by autologous stem cell transplantation (ASCT), which offers a cure to a minority of patients due to limitations in efficacy and eligibility. These data present the unmet need in the field, and this review article focuses on how second-generation chimeric antigen receptor T (CAR T) cell therapy targeting CD19 antigen may improve the outcomes with relapsed/refractory DLBCL. In heavily pretreated patients, who have dismal outcomes with conventional therapy, all three approved products-tisangenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel) have shown durable, unprecedented complete responses with the potential for cure. When compared to salvage regimens and ASCT as the standard of care, axi-cel and liso-cel, unlike tisa-cel, have demonstrated superiority in long-term control. In ASCT-ineligible r/r DLBCL, liso-cel has shown a favourable benefit-risk ratio. Regarding safety, two adverse events of interest have emerged: cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, both of which are manageable. Real-world evidence reflects the results of pivotal trials while favouring axi-cel in heavily pretreated patients, albeit with higher toxicity. The main barrier to the implementation of this treatment modality is the cost associated with the process of CAR T therapy, along with complications and reimbursement issues. However, the barriers can be overcome, and CAR T therapy has the potential to become the standard of care in relapsed/refractory DLBCL. Furthermore, with advances in the scientific engineering of CAR products and the understanding of novel treatment modalities currently being tested in clinical trials, we believe that targeted cellular therapy will become the future of relapsed/refractory DLBCL treatment.

Cytokine release syndrome (CRS) is a common, acute adverse event associated with T-cell redirecting therapies such as bispecific antibodies (BsAbs). The nature of CRS events data makes it challenging to capture an unbiased exposure-response relationship with commonly used models. For example, simple logistic regression models cannot handle traditional time-varying exposure, and static exposure metrics chosen at early time points and with lower priming doses may underestimate the incidence of CRS. Therefore, more advanced modeling techniques are needed to adequately describe the time course of BsAb-induced CRS. Herein, we present a two-part mixture model that describes the population incidence and time course of CRS following various dose-priming regimens of elranatamab, a humanized BsAb that targets the B-cell maturation antigen on myeloma cells and CD3 on T cells, where the conditional time-evolution of CRS was described with a two-state (i.e., CRS-yes or no) Markov model. In the first part, increasing elranatamab exposure (maximum elranatamab concentration at first CRS event time (Cmax,event)) was associated with an increased CRS incidence probability. Similarly, in the second part, increased early elranatamab exposure (Cmax,D1) increased the predicted probability of CRS over time, whereas premedication including corticosteroids and IL-6 pathway inhibitors use demonstrated the opposite effect. This is the first reported application of a Markov model to describe the probability of CRS following BsAb therapy, and it successfully explained differences between different dose-priming regimens via clinically relevant covariates. This approach may be useful for the future clinical development of BsAbs.

Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.

This phase 2 study evaluated mosunetuzumab plus cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin (Pola-M-CHP) vs Pola-rituximab (R)-CHP for first-line treatment of diffuse large B-cell lymphoma. Patients were randomized 2:1 to receive 6 cycles of Pola-M-CHP or Pola-R-CHP on day 1 of each 21-day cycle. Mosunetuzumab was administered intravenously via step-up dosing during cycle 1 and at 30 mg on day 1 of subsequent cycles. The primary end point was independent review committee-assessed complete response (CR) rate by positron emission tomography-computed tomography. Overall, 62 patients were enrolled and received Pola-M-CHP (n = 40) or Pola-R-CHP (n = 22). CR rates were similar in both arms (72.5% with Pola-M-CHP vs 77.3% with Pola-R-CHP); the 24-month investigator-assessed progression-free survival rate was 70.8% (95% confidence interval [CI], 55.6-86.1) with Pola-M-CHP vs 81.8% (95% CI, 65.7-97.9) with Pola-R-CHP. The most common adverse event (AE) was cytokine release syndrome (68.4%; mostly grade 1 [52.6%], and primarily confined to cycle 1) with Pola-M-CHP and neutropenia/neutrophil count decreased (54.5%) with Pola-R-CHP. Neutropenia/neutrophil count decreased was the most frequently observed grade ≥3 AE in both arms (Pola-M-CHP, 36.8%; Pola-R-CHP, 22.7%). Rates of grade ≥3 AEs (86.8% vs 59.1%), serious AEs (63.2% vs 13.6%), and AEs leading to treatment discontinuation (13.2% vs 0%) were higher with Pola-M-CHP than Pola-R-CHP, respectively. Pharmacodynamic changes were supportive of mosunetuzumab's mechanism of action and its addition to the Pola-CHP combination. Pola-M-CHP, although an active combination, did not demonstrate a clinical benefit over Pola-R-CHP in this small study. This trial was registered at www.clinicaltrials.gov as #NCT03677141.

This study aimed to investigate the safety and efficacy of fourth-generation combined PSMA and GD2-targeted chimeric antigen receptor (CAR)-T cells in the treatment of refractory/relapsed gliomas.

This study employed a single-arm design, enrolling patients with confirmed refractory/relapsed gliomas at the Immuno-oncology Department of the Cancer Center at Clifford Hospital in Guangdong. Eligible patients received combined treatment with PSMA CAR-T and GD2 CAR-T cells via intravenous administration. The dose of reinfused CAR-T cells ranged from 1-5 × 10^6 cells/kg of body weight.

Six patients were included in the study, all of whom responded to the treatment. The overall response rate (ORR) was 50%, with three patients achieving complete response (CR) (50%) and three demonstrating stable disease (SD) (50%). The median progression-free survival (PFS) was 9.0 months (range, 1-56 months), and the median overall survival (OS) was 24.5 months (range, 13-63 months). Three patients (50%) developed cytokine release syndrome (CRS), all of which were classified as grade I CRS, and no patients experienced immune effector cell-associated neurotoxicity Syndrome (ICANS).

Combined PSMA CAR-T and GD2 CAR-T cell therapy demonstrated significant efficacy and good tolerability in the treatment of refractory/relapsed gliomas, without severe adverse reactions.

High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double hit [HGBL-DH] or triple hit [HGBL-TH]) or not otherwise specified (HGBL-NOS) are considered to be more aggressive diseases among large B-cell lymphomas (LBCLs). CD19-targeting chimeric antigen receptor (CAR) T cells have changed the prognosis of chemoresistant LBCL. Clinical and pathological data of patients treated for relapsed/refractory LBCL or HGBL in third line or more, all characterized by fluorescence in situ hybridization, were collected from the French DESCAR-T registry. Between January 2018 and November 2022, a total of 228 patients were included across 14 centers, 73 with HGBL (28 HGBL-DH MYC-BCL2, 14 HGBL-TH, 8 HGBL-DH MYC-BCL6, and 23 HGBL-NOS) and 155 with non-HGBL. The median follow-up was 18.5 months (95% confidence interval [CI], 14.3-23.4) from the date of infusion. Progression-free survival and overall survival (OS) were not significantly different between HGBL and non-HGBL, at 3.2 months (95% CI, 2.8-6.0) vs 4.5 months (95% CI, 3.1-8.7; P = .103) and 15.4 months (95% CI, 5.6-32.4) vs 18.3 months (95% CI, 8.5 to not reached), respectively. From the date of eligibility, the median OS was inferior for patients with HGBL-TH/DH MYC-BCL2 at 6.6 months vs 18.5 months for HGBL-NOS vs 13.6 months for HGBL-DH MYC-BCL6 vs 11.8 months for LBCL (P = .037). However, patients who received infusion presented the same outcome. CAR T-cell therapy used in third line or more seems to overcome the poor prognosis of HGBL subtypes, especially in HGBL-TH/DH MYC-BCL2. This observation supports considering the potential benefit of using CAR T cells earlier in disease course.

Bispecific antibodies (BsAbs) are a new class of immunotherapeutic agents for patients with multiple myeloma (MM). Although this new class of drug is associated with good disease control, they are also associated with increased risk of infectious complications. Since endemic community-acquired and nosocomial infections vary across the globe, we conducted this study to report real-world data of infectious complications associated with BsAbs in Korean population.

We retrospectively reviewed all MM patients who received BsAb therapy between January 2021 and January 2024 at Seoul National University Hospital. We identified 61 patients who underwent BsAb therapy at our center with median follow-up of 34 weeks (95% confidence interval, 25.85-55.85). Thirty-three patients (54%) received B-cell maturation antigen (BCMA)-targeting BsAb, and 30 (49%) received combination therapy.

Of the 61 patients, 39 (64%) had at least one episode of infection. A total of 69 infections affecting patient management occurred during the study period, 3% grade 1 infection, 8% grade 2, 72% grade 3, 8% grade 4 and 8% grade 5. The most common type of infection was lower respiratory tract infection (n = 32/69, 46%), followed by systemic infection (n = 21/69, 30%). Etiology wise, viral infections were most common (67%), followed by fungal infections (13%) and bacterial infections (10%). Among viral infections, cytomegalovirus (CMV) was most common. Patients treated with BCMA-targeting BsAb or combination therapy were associated with higher incidence of CMV reactivation and clinically significant CMV infection.

Particular pattern of infectious complications including CMV infection was noted in Korean patients. Identifying and determining the nature of infectious disease dynamics is becoming increasingly important for optimal resource allocation and shaping healthcare policies. In this regard, our first-in-Asian population study holds its value.

Historically, the presence of measurable disease has been considered essential to stimulate CAR T-cell expansion and persistence. However, the kinetics of CAR T cells in patients achieving complete response (CR) before infusion remain poorly understood. This study aimed to evaluate the outcomes and CAR T-cell kinetics in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients stratified by pre-infusion disease status. In this retrospective analysis of 87 patients treated at a single institution, 23 (26.4%) were in CR and 64 (73.6%) were in non-CR prior to CAR T-cell infusion. Patients in CR exhibited significantly better progression-free survival (PFS) and overall survival compared to non-CR patients. Peripheral blood CAR T-cell kinetics, including the proportion and absolute counts of CAR T cells, CD4+ CAR T cells and CD8+ CART cells, showed no significant differences between CR and non-CR groups. These findings were consistent across different CAR T-cell products, whether 4-1BB- or CD28-based. Moreover, an analysis of patients achieving complete metabolic response (CMR) by PET-CT confirmed comparable CAR T-cell expansion and persistence in both CMR and non-CMR patients. Our findings demonstrate that CAR T-cell therapy achieves robust expansion and favourable survival outcomes in CR patients, even in the absence of measurable disease.

Chimeric antigen receptor therapy (CAR-T therapy) is a genetically engineered cellular therapy that is currently integrated into the management of hematological malignancies. Institutions treating patients with CAR-T therapy need to establish a framework of delivery that covers all the main components of the patient journey including intake of patients into the program from referring centers, patient selection according to established eligibility criteria, apheresis, logistics, bridging therapy, infusion and post-infusion care. A CAR-T therapy program, with its unique requirements, needs to be delivered by a multidisciplinary team (MDT). Prior to the establishment of the program, a well-structured business plan should be developed with a clear financial and/or reimbursement model. Consideration should be given to the overall capacity and staffing requirements. Standard operating procedures and guidelines are vital for ensuring that quality standards are clearly defined and adhered to. Institutions should develop a research plan for CAR-T that may incorporate not only industry sponsored trials but also in-house CAR-T manufacture of investigational CAR-T constructs. This report presents recommendations from a group of international experts highlighting the priorities and considerations when developing a new CAR-T program.

Few studies have thoroughly evaluated the symptom burden and quality of life (QOL) among patients diagnosed with hematologic malignancies who underwent chimeric antigen receptor T-cell (CAR-T) therapy. In total, 97 eligible patients completed the Functional Assessment of Cancer Therapy generic scale (FACT-G) at week 4 after CAR-T cell infusion. We used the Common Terminology Criteria Adverse Events (CTCAE) to measure symptom burden of CAR-T patients during the same period. We studied factors associated with QOL using liner regression analysis. During the period of hospitalization after CAR-T treatment, the prevalence of self-reported symptoms among CAR-T patients was highest for fatigue (89.7%), followed by sleep disorders (79.4%) and decreased appetite (66.0%). And the mean score of FACT-G was 69.06 (SD = 13.88). Liner regression analysis showed that decreased appetite (β = -0.30, 95% CI = -7.48 to -1.83, P = 0.002), fatigue (β = -0.28, 95% CI = -7.23- -1.69, P = 0.002), nausea (β = -0.26, 95% CI = -10.50 to -2.16, P = 0.003) and a history of hematopoietic stem cell transplantation (HSCT) (β = -0.21, 95% CI = -13.38- -1.56, P = 0.014) were associated with poorer quality of life. The symptom burden experienced by patients undergoing CAR-T treatment is substantial during their hospitalization, and it is closely associated with a diminished quality of life. It is imperative for clinical medical staff to be attentive to the symptom burden of CAR-T patients and to enhance the effectiveness of symptom management interventions.

T cell engagers (TCEs) are transformational oncology therapies but are limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce fewer cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs). However, why NK cells secrete fewer cytokines, such as tumor necrosis factor (TNF), and how NKCEs perform directly against TCEs remains unclear. Here, we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate interleukin (IL)-2, thereby increasing their potency and durability. Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and distinct therapeutic benefits. Our results provide a blueprint for the development of multifunctional NKCEs, which may serve as an alternative to current TCE therapies.

Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.

Chronic inflammatory demyelinating polyneuropathy (CIDP) presents a significant therapeutic challenge, with up to 15% of patients being refractory to first-line treatments.

Anti-B cell maturation antigen chimeric antigen receptor T (CAR-T) cell therapy was applied to two patients with highly relapsed and refractory CIDP, followed by safety and efficacy evaluation. Multi-omics analyses were performed on samples of peripheral blood mononuclear cells (PBMCs) collected before and after infusion.

Both patients had no severe adverse events and achieved drug-free remission within 6 months post-CAR-T therapy. Patient 1 experienced disease recurrence 12 months post infusion following a severe infection of COVID-19, while patient 2 maintained remission over 24 months. Relapse was accompanied by reactivation of pathogenic B cells and recurrence of autoantibodies/peptides targeting axons or myelin. Metabolic reprogramming of B cells characterized by overglycolysis was linked to disease relapse, which could be modulated by regulatory factor X5.

This study demonstrates the safety and potential of anti-BCMA CAR-T cell therapy in treating refractory CIDP and provides insights into the molecular mechanisms underlying patient responses (ClinicalTrials.gov: NCT04561557).

Ministry of Science and Technology China Brain Initiative grant STI2030-Major Projects 2022ZD0204700 (to W.W.), National Natural Science Foundation of China grants 82371404 and 82071380 (to D.-S.T.) and 82471353 and 82271341 (to C.Q.), Knowledge Innovation Program of Wuhan Shuguang Project 2022020801020454 (to C.Q.), and Key Research and Development Program of Hubei Provincial Department of Science and Technology 2023BCB148 (to D.-S.T.). The clinical trial was funded by Nanjing IASO Biotechnology Co., Ltd.

Prognosis after salvage allogeneic hematopoietic cell transplantation (HCT) in refractory myeloid malignant diseases is poor with no standard of care.

A prospective single-arm study was conducted to evaluate if a combination of posttransplantation bendamustine and cyclophosphamide (PTBCy) facilitates augmented graft-vs-leukemia effect in this group of patients. The prospective study (NCT04943757) of HCT from all types of donors enrolled 50 patients with refractory myeloid neoplasms.

Cumulative incidence of engraftment was 88%; 76% had no measurable residual disease. Immune toxicity in the form of cytokine release syndrome was observed in 30%. Cumulative incidence of acute graft-vs-host disease (GVHD) Grade 2 through 4 was 20%. Cumulative incidence of moderate and severe chronic GVHD was 34%. Nonrelapse mortality was 20%. Relapse incidence was 62%, but median time to relapse was 245 days. Overall survival was 33% and event-free survival was 22%. In the multivariate analysis of event-free survival alternative donor (hazard ratio, 0.24; 95% CI, 0.11-0.52) and adverse genetic features (hazard ratio, 2.48; 95% CI, 1.26-4.88) were significant. PTBCy regimen was associated with unique immune reconstitution pattern with high levels of CD8+ effector memory T cells, PD-1L-positive monocytes, and granulocytes.

PTBCy GVHD prophylaxis is a promising approach for refractory myeloid neoplasms, which delays relapse after HCT and opens the window for posttransplant prophylaxis.

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an interleukin-1 (IL-1) receptor antagonist, to prevent CRS/NT that would require hospitalization (grade ≥2) in patients receiving axicabtagene ciloleucel for large-cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study, in line with others, demonstrates that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most patients. As part of the initial study design, we prospectively incorporated single-cell RNA sequencing to gain insight into the molecular immune signaling associated with breakthrough CRS and NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that interferon gamma (IFN-γ) pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFN-γ and CXCL10 in CD14+ monocytes. This correlated with increased IFN-γ and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade ≥2 toxicities, regardless of anakinra treatment. These data identify IFN-γ as a potential key mechanism in CAR-T-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable. This trial was registered at www.ClinicalTrials.gov as #NCT04150913.

Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.

Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with neurotoxicity, which may include acute symptomatic seizures (ASySs). Specific risk factors and short-term and long-term outcomes of ASyS associated with CAR T-cell therapy have not been well investigated.

This retrospective cohort study evaluated incidence and risk factors for ASyS during CAR T-cell therapy. We included patients treated at Mayo Clinic in Minnesota, Florida, and Arizona who underwent CAR T-cell therapy for hematologic malignancies from October 2019 to November 2023. Pretreatment demographics, clinical information, type of CAR T-cell therapy, neuroimaging, laboratories during treatment, and clinical features during admission were analyzed. Data on treatment and prevalence of seizures, EEG, and survival at the last follow-up were assessed. T-tests and nonparametric testing were performed on categorical and continuous data, respectively. Multivariable analysis was also performed.

We included 180 patients (mean age 62.3 years, 57.2% women) with 8 (4.4%) developing ASyS at a mean of 8.0 ± 5.3 days after therapy. Earlier onset of cytotoxic release syndrome (odds ratio [OR] 1.81, 95% CI 0.62-2.99, p = 0.007), higher grade immune effector cell-associated neurotoxicity syndrome (ICANS) (OR -1.43, 95% CI -1.86 to -1.00, p < 0.001), focal neurologic deficits (OR 7.15, 95% CI 1.60-32.14, p = 0.007), and cefepime (OR 0.58, 95% CI 0.51-0.65, p = 0.022) exposure were significantly associated with a higher risk of ASyS. A multivariable model accounting for age and sex fit best using the lowest minimum immune effector cell encephalopathy score and highest ICANS grade (R2 = 0.555, χ2 = 28.507, p < 0.001). ASyS was associated with death at the last follow-up (OR 0.48, 95% CI 0.41-0.56, p = 0.007), although short-term outcomes were not affected by ASyS. Nonprotocolized antiseizure medication (ASM) prophylaxis did not affect ASyS incidence.

This study suggests a low risk of ASyS because of CAR T-cell therapy, with certain risk factors that may be predictive of ASyS and lack of a definitive and direct association of ASyS with outcomes. The current approach to ASM prophylaxis should be reconsidered when ICANS is encountered. This study is limited by its retrospective nature and the use of ASM prophylaxis in all patients with ICANS, which requires further study to assess its necessity.

Immediate side effects after chimeric antigen receptor (CAR) T-cell therapy are well documented and include cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity (ICANS). However, long-term patient-reported outcomes are understudied. Using a social determinants of health (SDoH) framework, we described the long-term health-related quality of life (HRQoL), cognitive function, and symptom burden of patients in sustained remission after CAR T-cell therapy and examined the relationship between acute CRS and ICANS and long-term cognitive function and symptom burden.

This cross-sectional study included adults in remission after CAR T-cell therapy for multiple myeloma or B-cell lymphoma who were within 1-5 years post-treatment. We used bivariate analyses to measure associations between clinical and SDoH variables and long-term outcomes and linear regression to examine the relationship between ICANS and CRS toxicity and longer-term outcomes.

Participants (n = 58) were a median of 67 years of age (22-88), 72% had lymphoma, 28% had multiple myeloma, and they were a median of 2 years (1-4.7) post-CAR T-cell infusion. Most of the participants reported good HRQoL. Over one third of participants reported mild-to-moderate impairment in physical function, social roles and activities, or pain domains. Higher income and employment were significantly associated with better physical HRQoL (P < .05). Participants reported low symptom burden, with fatigue most commonly reported. Neither CRS nor ICANS toxicity predicted long-term cognitive function or symptom burden.

Patients in long-term remission after CAR T-cell therapy have good HRQoL and cognitive function with minimal symptom burden. Importantly, there was no relationship between CRS and ICANS and long-term symptom burden or cognitive function. Results support the long-term clinical benefit of CAR T-cell therapy.

Blinatumomab is a bispecific T-cell engager approved for the treatment of relapse/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Most studies evaluating blinatumomab were conducted in Caucasian populations, with limited data available in Chinese patients. This retrospective study aims to evaluate the efficacy and safety of blinatumomab in Chinese patients with R/R B-ALL.

A total of 19 patients (10 males, 9 females) with a median age of 49 years (range: 9-66) who received blinatumomab treatment at the Aerospace Center Hospital between November 2021 and November 2024 were included. Rates of complete remission (CR) and minimal residual disease (MRD) response, 1-year overall survival (OS) and relapse-free survival (RFS), and adverse events were analyzed.

The median number of blinatumomab cycles administered was 1 (range: 1-6). Twelve (80.0%, 95% confidence interval [CI]: 51.9-95.7) of the 15 patients with overt marrow disease achieved CR, with 8 achieving MRD negativity. Four patients with < 5% blast but positive MRD all sustained CR and achieved MRD negativity. The overall MRD response rate was 63.2% (12/19, 95%CI: 38.4-83.7). The 1-year overall survival (OS) and relapse-free survival (RFS) rates were 64.2% ± 12.1% and 73.3% ± 11.4%, respectively. MRD responders had significantly better OS compared to MRD non-responders (log-rank test, P = 0.023). Of the 16 patients with CR, 62.5% proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The most frequent adverse event was cytokine release syndrome, which occurred in 11 patients (10 with grade 1-2 and 1 with grade 3 severity).

Blinatumomab is both effective and well-tolerated in Chinese patients with R/R B-ALL, achieving high rates of CR and MRD negativity and facilitating more patients' eligibility for allo-HSCT.

The bispecific antibody talquetamab demonstrated substantial responses in heavily pretreated relapsed or refractory multiple myeloma (RRMM) in the global phase 1/2 MonumenTAL-1 study. This study, evaluated the safety and efficacy of talquetamab in Japanese patients with RRMM pretreated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. The primary endpoints were frequency and type of treatment-emergent adverse events (TEAEs) and serious AEs including dose-limiting toxicity (DLT). The secondary endpoints were overall response (ORR; partial response or better), duration of, and time to response. At data cutoff, 15 patients had received subcutaneous talquetamab at three doses (Cohort 1: 135 µg/kg weekly [QW, n = 4]; Cohort 2: 400 µg/kg [QW, n = 5]; Cohort 3: 800 µg/kg [Q2W, n = 6]). No DLTs, deaths, or AE-related dose reductions/treatment discontinuation were observed. Common TEAEs were neutropenia (60.0%), lymphopenia (53.3%), and CRS (46.7%). TEAEs of clinical interest (all Grade ≤ 2) were dysgeusia, skin toxicity, nail disorder, and dry mouth. With an overall median follow-up of 9.0 months, the ORR was 60.0% (95% confidence interval 32.3%, 83.7%). Talquetamab showed substantial responses in Japanese patients with RRMM, consistent with the global MonumenTAL-1 study, supporting its potential as a new standard of care for Japanese RRMM patients.

Teclistamab, a BCMA-directed bispecific antibody, received regulatory approval for relapsed/refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. Despite the fact that myeloma is primarily a cancer of elderly adults, only 15% of MajesTEC-1 participants (n = 24) were ≥75 years old. In this multicenter retrospective study, we report real-world outcomes of a large cohort of older RRMM patients treated with teclistamab. Of 385 analyzed patients, 83 (22%) were in the older group (age ≥75) and 302 (78%) in the younger group (age <75). Compared to the younger group, the older group had less adverse baseline disease characteristics, including a lower incidence of high-risk cytogenetics (44.6% vs. 57.9%, p = 0.03) and extramedullary disease (22% vs. 40%, p = 0.02). There were no significant differences in rates of any-grade CRS (52% vs. 59%, p = 0.27), any-grade ICANS (19% vs. 13%, p = 0.12), and overall response rate (62% vs. 53%, p = 0.17) between the older and younger groups. In multivariable analysis, age was not significantly associated with survival outcomes. Our findings suggest that teclistamab is safe and efficacious in well-selected patients ≥75 years old, and advanced age alone should not preclude teclistamab administration.