B-cell Hematologic Malignancies Research Articles

A lesson from fatal invasive fungal infections after CAR-T cell therapy: a case report and literature review.

CD19 chimeric antigen receptor T (CAR-T) cell therapy represents an effective approach to treating patients with relapsed or refractory B-cell hematologic malignancies. Nevertheless, owing to the immunosuppressive effects of this regimen, patients undergoing CD19 CAR-T cell therapy may face an elevated risk of invasive fungal infections, which involve fungi penetrating the host's tissues or bloodstream, leading to life-threating infectious diseases. Herein, we present the case of a 17-year-old male diagnosed with acute lymphoblastic leukemia, who subsequently experienced a fatal invasive fungal infection following administration of CAR-T cell therapy. Furthermore, we delve into the identification of risk factors, implementation of preventive measures and exploration of therapeutic interventions for invasive fungal infections after CAR-T cell therapy.

CT-244 Updated Clinical Progress of IL-10 expressing CD19 CAR-T Cells for Treatment of Relapsed or Refractory B-Cell Hematological Malignancies at Tiny Doses

CT-244 Updated Clinical Progress of IL-10 expressing CD19 CAR-T Cells for Treatment of Relapsed or Refractory B-Cell Hematological Malignancies at Tiny Doses

Updated Clinical Progress of IL-10 expressing CD19 CAR-T Cells for Treatment of Relapsed or Refractory B-Cell Hematological Malignancies at Tiny Doses

Updated Clinical Progress of IL-10 expressing CD19 CAR-T Cells for Treatment of Relapsed or Refractory B-Cell Hematological Malignancies at Tiny Doses

The Role of Chimeric Antigen Receptor T-Cell Therapy in Immune-Mediated Neurological Diseases.

Despite the use of 'high efficacy' disease-modifying therapies, disease activity and clinical progression of different immune-mediated neurological diseases continue for some patients, resulting in accumulating disability, deteriorating social and mental health, and high economic cost to patients and society. Although autologous hematopoietic stem cell transplant is an effective treatment modality, it is an intensive chemotherapy-based therapy with a range of short- and long-term side-effects. Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of B-cell and other hematological malignancies, conferring long-term remission for otherwise refractory diseases. However, the toxicity of this treatment, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and the complexity of production necessitate the need for a high level of specialization at treating centers. Early-phase trials of CAR-T therapies in immune-mediated B cell driven conditions, such as systemic lupus erythematosus, neuromyelitis optica spectrum disorder and myasthenia gravis, have shown dramatic clinical response with few adverse events. Based on the common physiopathology, CAR-T therapy in other immune-mediated neurological disease, including multiple sclerosis, chronic inflammatory polyradiculopathy, autoimmune encephalitis, and stiff person syndrome, might be an effective option for patients, avoiding the need for long-term immunosuppressant medications. It may prove to be a more selective immunoablative approach than autologous hematopoietic stem cell transplant, with potentially increased efficacy and lower adverse events. In this review, we present the state of the art and future directions of the use of CAR-T in such conditions. ANN NEUROL 2024;96:441-452.

Risk of gastrointestinal adverse events associated with chimeric antigen receptor T-cell therapy (CAR-T): A nationwide analysis.

e19505 Background: Chimeric antigen receptor T-cell therapy (CAR-T) has been successfully used and has improved outcomes in the treatment of B-cell hematological malignancies and multiple myeloma. There is evidence that unique serious adverse events like cytokine release syndrome (CRS) and Immune effector cell associated neurotoxicity syndrome (ICANS) are associated with CAR-T. Gastrointestinal adverse events (GI-AE) are commonly observed after CAR-T, although they are not well characterized. In the analysis, we summarized the incidence of gastrointestinal adverse events (GI-AE) and mortality associated with CAR-T with or without CRS. Methods: We conducted a retrospective cohort study using the 2020 Nationwide Inpatient Sample database, which is the largest nationally representative inpatient database in the United States. The dataset is weighted to obtain national estimates, and ICD-10 was utilized to identify admissions for CAR-T. The primary outcome is in-hospital mortality, and secondary outcomes are GI-AE associated with CAR-T with or without CRS and length of stay (LOS). Odds ratio (OR) and Mean difference (MD) were adjusted for confounders like comorbidities and sociodemographics using multivariate regression analysis. Results: There were 32 million weighted discharges in the 2020 NIS database; a total of 1950 cases were identified receiving CAR-T therapy with a mean age of 56.53, male 60.51%, and white race 74.8%. In our study, 40.25% had GI-AE, 15.38% had CRS and 13.8% had ICANS. The most common GI-AE was nausea and vomiting (23.84%). Other GI-AE were diarrhea (9.5%), colitis (8.2%), peptic ulcer disease (2.9%), hepatic failure (1.28%), and pancreatitis (2.2%). 68 (3.85%) patients died after receiving CAR-T. The results revealed that CAR-T with GI-AE was not significantly associated with in-hospital mortality (adjusted OR = 1.12, 95% CI: 0.29-4.24), and LOS (adjusted mean difference = 3.38, 95% CI: -0.91-7.67) compared to CAR-T without GI-AE. Liver failure is significantly associated with the highest mortality after CAR-T (OR = 46.62, 95% CI: 6.9-315). Conclusions: The national survey reveals that predominantly GI-AE are mild including nausea, vomiting, and diarrhea. GI-AE related with CAR-T had similar outcomes including mortality and LOS compared to CAR-T without GI-AE. The risk of mortality becomes higher when CAR-T complicated by hepatic failure. [Table: see text]

Expanding the role of CAR T-cell therapy: From B-cell hematological malignancies to autoimmune rheumatic diseases.

Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy where the lymphocytes, mostly T-cells, are redirected to specifically recognize and eliminate a target antigen by coupling them with CARs. The binding of CAR and target cell surface antigens leads to vigorous T cell activation and robust anti-tumor immune responses. Areas of implication of CAR T-cell therapies include mainly hematological malignancies (i.e., advanced B-cell cancers); however, recent studies have proven the unprecedented success of the new immunotherapy also in autoimmune rheumatic diseases. We aim to review the recent advances in CAR T-cell therapies in rheumatology but also to address the limitations of their use in the real clinical practice based on the data on their efficacy and safety.

COVID-19-associated pulmonary aspergillosis (CAPA) in hematological patients: Could antifungal prophylaxis be necessary? A nationwide study

BackgroundCOVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a relatively common complication. Multiple studies described this relationship in critical patients, however its incidence and outcome in other risk groups such as immunosuppressed patients remains unknown. In this sense, we aimed to evaluate the rates and outcomes of CAPA in hematological patients and according to the different hematological malignances, comparing to invasive pulmonary aspergillosis (IPA) in non-COVID-19 ones. MethodsNationwide, population-based and retrospective observational cohort study including all adult patients with hematological malignancies admitted in Spain since March 1, 2020 to December 31, 2021. The main outcome variable was the diagnosis of IPA during hospitalization in hematological patients with or without COVID-19 at admission. The rate of CAPA compared to IPA in non-COVID-19 patients in each hematological malignancy was also performed, as well as survival curve analysis. FindingsCOVID-19 was diagnosed in 3.85 % (4367 out of 113,525) of the hematological adult inpatients. COVID-19 group developed more fungal infections (5.1 % vs. 3 %; p < 0.001). Candida spp. showed higher rate in non-COVID-19 (74.2 % vs. 66.8 %; p = 0.015), meanwhile Aspergillus spp. confirmed its predominance in COVID-19 hematological patients (35.4 % vs. 19.1 %; p < 0.001). IPA was diagnosed in 703 patients and 11.2 % (79 cases) were CAPA. The multivariate logistic regression analysis found that the diagnosis of COVID-19 disease at hospital admission increased more than two-fold IPA development [OR: 2.5, 95CI (1.9–3.1), p < 0.001]. B-cell malignancies – specifically B-cell non-Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukemia and acute lymphoblastic leukemia – showed between four- and six-fold higher CAPA development and 90-day mortality rates ranging between 50 % and 72 %. However, myeloid malignancies did not show higher CAPA rates compared to IPA in non-COVID-19 patients. ConclusionCOVID-19 constitutes an independent risk factor for developing aspergillosis in B-cell hematological malignancies and the use of antifungal prophylaxis during hospitalizations may be warranted.

Abstract LB236: Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses

Abstract Background: The undeniable success of CD19 CAR-T cell therapy in managing relapsed or refractory (r/r) B-cell hematological malignancies, such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL), underscores its significance. Despite the favorable complete remission (CR) rates of around 50% for r/r DLBCL and up to 90% for r/r B-ALL, a notable challenge persists as more than half of patients experiencing CR after CD19 CAR-T cells treatment encounter relapse within a year, attributed to inadequate CAR-T persistence in both indications. Urgent attention is required to devise innovative strategies to overcome these challenges. Recently, we developed metabolically armed CD19 CAR-T cells expressing IL-10 can enhance OXPHOS metabolism, proliferation, and persistence of CAR-T cells in vivo. Significantly, these IL-10-expressing CAR-T cells trigger stem-like memory responses in various lymphoid organs, leading to robust tumor eradication and durable protection. Motivated by these promising findings, an open-label, single arm, investigator-initiated trial (IIT, ClinicalTrials.gov identifier: NCT05715606, NCT05747157) was conducted to assess the safety and efficacy of newly developed metabolically armed IL-10-expressing CD19 CAR-T (product name: Meta10-19 infusion) for treating patients with r/r DLBCL or r/r B-ALL. Method: From Feb 2023 to Dec 2023, this IIT clinical trial evaluated Meta10-19 infusion in adult patients with r/r DLBCL or r/r B-ALL. The patients were recruited and treated at the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China. Patients in 3 dose cohorts (2.0 × 104, 5.0 × 104, or 1.0 × 105 CAR-T cells/kg, corresponding to 1%, 2.5%, or 5% doses of commercialized CAR-T infusion) underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine before Meta10-19 infusion. The primary endpoint was the incidence of dose-limiting toxicities. The secondary endpoint was the response and survival. Results: The treatment with Meta10-19 infusion has successfully induced CR in all 12 cases of r/r DLBCL (n=6) or r/r B-ALL (n=6), as evaluated by PET-CT scan, NMR spectroscopy or minimal residual disease assessment of bone marrow. No server cytokine storm syndrome or neurotoxicity was observed. All treated patients achieved CR at 3 months post treatment, with the first patient maintaining continuous remission up to 9 months until now. Notably, these metabolically armed CD19 CAR-T cells demonstrated efficacy even for patients with bulky mass (≥7.5 cm) of DLBCL at extremely low infusion dose (1~5% doses of commercialized CAR-T). Conclusion: Preliminary findings suggest that Meta10-19 infusion exhibits promising breakthrough efficacy and safety profile, and active enrollment is ongoing to validate the initial results. Citation Format: Yugang Guo, Qianwen Xu, Lei Xue, Erling Chen, Chonglin Liu, Min Gao, Youjia Li, Jingjing Ren, Jinping Li, Li Tang, Xingbing Wang. Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB236.

Leukemia cancer cells and immune cells derived-exosomes: Possible roles in leukemia progression and therapy.

Exosomes have a significant impact on tumor survival, proliferation, metastasis, and recurrence. They also open up new therapeutic options and aid in the pathological identification and diagnosis of cancers. Exosomes have been shown in numerous studies to be essential for facilitating cell-to-cell communication. In B-cell hematological malignancies, the proteins and RNAs that are encased by circulating exosomes are thought to represent prospective sources for therapeutic drugs as well as biomarkers for diagnosis and prognosis. Additionally, exosomes can offer a "snapshot" of the tumor and the metastatic environment at any given point in time. In this review study, we concluded that leukemia-derived exosomes could be utilized as prognostic, diagnostic, and therapeutic biomarkers for individuals suffering from leukemia. Moreover, clinical studies have demonstrated that immune cells like dendritic cells create exosomes, which have the ability to activate the immune system against leukemia.

Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo.

Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy. We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen. Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine, followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy, exerts the most efficacious therapeutic effect in B-cell hematological malignancies. Concurrently, RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism, primarily through the inhibition of key mitochondrial targets, such as C-Jun Kinase enzyme (C-JUN). In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

Efficacy of Multiple SARS-CoV-2 Vaccine Doses in Patients with B Cell Hematologic Malignancies Receiving Chimeric Antigen Receptor T Cell Therapy: A Contemporary Cohort Analysis

The mortality due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) approaches 40% in recipients of chimeric antigen receptor (CAR) T cell therapy (CAR-T). The efficacy of repeated vaccine doses, including bivalent boosters, remains unknown. We examined the efficacy of repeated vaccine doses among CAR-T recipients who received at least 2 or more vaccine doses after T cell infusion. This single-center retrospective study included adults age >18 years receiving CAR-T for relapsed/refractory (R/R) B cell hematologic malignancies targeting CD19, BCMA, or CD19 and CD20 between September 2018 through March 2022 and were alive beyond 2021 to receive incremental SARS-CoV-2 vaccine doses with available seroconversion data. Multivariable analyses were performed using the design-adjusted Cox regression and logistic regression approaches with stratification. In multivariable analysis, seroconversion rates were significantly greater with a total of 4 or more vaccine doses (odds ratio [OR], 8.22; P = .008). CAR-T recipients with other B cell hematologic malignancies had significantly lower seroconversion rates and diminished Ab titers compared to those with R/R multiple myeloma (OR, .07; P = .003). One patient died due to COVID-19 in this vaccinated study cohort, accounting for a COVID-19-attributable mortality rate of 1.7%. The results provide baseline vaccine response data in a contemporary cohort including patients with diverse group of SARS-COV2 variants and support the latest Centers for Disease Control and Prevention guidelines for repeated vaccinations directed against the prevalent variant of concern.

An interdisciplinary approach to the management of oncohematological patients with immunodeficiency: clinical cases. A review

Immunodeficiency occurs when one or more immune system components do not function properly, resulting in the body's inability to resist mostly infectious agents. Most cases of immunodeficiency in adults are acquired (secondary), but congenital immunodeficiencies are not uncommon. Primary immunodeficiencies are a heterogeneous group of innate immune errors that result in various clinical and laboratory manifestations. In contrast, secondary immunodeficiencies involve an acquired decrease in immune cell count and/or impairment of their function, commonly associated with an antibody level decrease. Secondary immunodeficiency in patients with B-cell hematological malignancies is a common condition attributed to both hematological malignancy and secondary antitumor therapy-related causes. Paradoxically, immunodeficiency, initially attributed to secondary causes, may be due to a previously undiagnosed primary immunodeficiency. Early diagnosis of immunodeficiency and optimization of management strategies with a multidisciplinary approach are critical to providing the most effective specific treatments and reducing the incidence of infection-related complications and mortality. The article addresses clinical practice, recommendations, and problems of immunodeficiency diagnosis and the effectiveness of immunoglobulin replacement therapy illustrated by clinical cases.

Long-Term Follow-up of Humanized and Murine CD19 CAR-T Cell Therapy for B-Cell Malignancies

Aim: CD19 chimeric antigen receptor T cell (CAR-T) therapy is a revolutionary treatment for relapsed/refractory (R/R) B-cell hematologic malignancies. However, the safety and efficacy of murine CAR-T cells which have been widely used as commercialized products still need to be improved. Similarly, murine CAR-T encountered the problem that CAR-related immunogenicity existed after the infusion, which led to the failure of the re-infusion of CAR-T cells. As an improved generation of murine CAR-T cells, whether humanized CAR-T therapy can overcome the above shortcomings remains to be explored. Methods: In this study, the differences in safety, efficacy, and long-term follow-up results of murine and humanized CD19 CAR-T cells in patients with B-cell malignancies were collected and analyzed. A total of 130 patients were enrolled, including 35 patients with murine CAR-T and 95 with humanized CAR-T cells (NCT 02965092, NCT 04008251). Results： The proportion of patients with cytokine release syndrome (CRS) in the murine and humanized groups was 54.3%（19/35） and 61.1%（58/95）, respectively. A significantly higher proportion of patients suffered from severe CRS in the murine group than that in the humanized CAR-T group (17.14% vs. 7.4%, P=0.0233), and one patient in each group died of Grade 5 CRS. The incidence of grade 1-2 Immune effector cell-associated neurotoxicity syndrome (ICANS) was 11.4% (murine: 4/35) and 5.3% (humanized: 5/95), but high-grade ICANS was not observed. Among patients receiving murine CAR-T cells, 80% achieved objective response (OR), 71.43% achieved complete response (CR) and the CR rate of patients with leukemia was 74.19%. The OR rate and CR rate of patients in the humanized group were 75.79% and 63.16%, respectively, while the CR rate of patients with leukemia receiving humanized CAR-T cells was 89.58%. The median follow-up time of patients in the murine and humanized groups was 7 months (0.6-75 months) and 5.5 months (0.5-34 months), respectively. The median progression-free survival (PFS) of patients with murine CAR-T cells was 11 months and that of patients with humanized CAR-T products was 12 months. Both of the median overall survival (OS) were not reached. Among the 48 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a higher OS rate (84.64% vs. 59.26%, P=0.1479) and a significantly improved PFS (43.94% vs. 33.33%, P=0.0217, Figure 1). Bridging transplantation was an independent factor in prolonging OS (x 2=8.017, p=0.0046) and PFS (x 2=6.584, p=0.0103) of patients with leukemia. Neither species of chimeric antigen receptor nor common risk factors such as age, recurrence, bone marrow burden, BCR-ABL fusion gene had significant effect on patients' long-term follow-up outcomes (Table 1). Four patients received CAR-T therapies more than once. Three of them still achieved varying degrees of long-term remission after multiple humanized CAR-T infusions. However, one patient relapsed as soon as one month after his second infusion of murine CAR-T cells. Conclusion: Results indicate that humanized CAR-T therapy showed better safety and durable efficacy, especially in patients with higher tumor burden in bone marrow. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients' failures of CAR-T therapies.

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis.

The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR-T) cells in the management of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR-T-cell persistence are the leading causes of progressive disease following single-antigen targeting, we evaluated CD22/CD19 dual-targeting CAR-T-cell therapy efficacy and safety in relapsed/refractory B-cell malignancies. The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B-cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19-dual-targeting CAR-T-cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random-effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1-year proportions of overall survival (OS) and progression-free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1-year OS and 1-year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual-targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19-CAR-T cells and third-generation CAR-T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment-related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Our meta-analysis demonstrated that the CD22/CD19 dual-targeting CAR-T-cell strategy has high efficiency with tolerable adverse effects in B-cell malignancies.

A Predictive Model of Severe Cytokine Release Syndrome After Coadministration of CD19- and CD22-Chimeric Antigen Receptor T-Cell Therapy in Children With B-Cell Hematological Malignancies Based on Patient-Reported Outcomes.

Chimeric antigen receptor T-cell therapy-related severe cytokine release syndrome (sCRS) has seriously affected the life safety of patients. To explore the influencing factors of sCRS in children with B-cell hematological malignancies and build a risk prediction model. The study recruited 115 children with B-cell hematological malignancies who received CD19- and CD22-targeted chimeric antigen receptor T-cell therapy. A nomogram model was established based on symptomatic adverse events and highly accessible clinical variables. The model discrimination was evaluated by the area under the receiver operating characteristic curve. The calibration of our model was evaluated by the calibration curve and Hosmer-Lemeshow test. The bootstrap self-sampling method was used to internally validate. Thirty-seven percent of the children experienced sCRS. Indicators included in the nomogram were tumor burden before treatment, thrombocytopenia before pretreatment, and the mean value of generalized muscle weakness and headache scores. The results showed that the area under the receiver operating characteristic curve was 0.841, and the calibration curve showed that the probability of sCRS predicted by the nomogram was in good agreement with the actual probability of sCRS. The Hosmer-Lemeshow test indicated that the model fit the data well (χ2 = 5.759, P = .674). The concordance index (C-index) obtained by internal validation was 0.841 (0.770, 0.912). The nomogram model constructed has a good degree of discrimination and calibration, which provides a more convenient and visual evaluation tool for identifying the sCRS. Incorporation of patient-reported outcomes into risk prediction models enables early identification of sCRS.

Hepatitis B Virus Reactivation in Patients Receiving Bruton Tyrosine Kinase Inhibitors.

Bruton tyrosine kinase (BTK) inhibitors are used to treat B-cell hematologic malignancies. Ibrutinib has been associated with hepatitis B virus (HBV) reactivation. We sought to identify patients with hematologic malignancies who developed HBV reactivation after receiving first-generation (ibrutinib) or second-generation (acalabrutinib and zanubrutinib) BTK inhibitors. We retrospectively studied all consecutive patients with hematologic malignancies with past HBV infection (HBV surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) or chronic HBV infection (HBsAg positive and anti-HBc positive) treated with BTK inhibitors at our institution from November 1, 2015, through November 1, 2022. Of 82 patients initially identified, 53 were excluded (11 because of false-positive anti-HBc results, and 42 because they were receiving anti-HBV prophylaxis owing to recent receipt of anti-CD20 monoclonal antibodies). The 29 remaining patients were further analyzed and 3 (10%; 2/28 with past and 1/1 with chronic HBV infection) were found to have HBV reactivation. One patient received ibrutinib, and 2 received acalabrutinib. All developed HBV-associated hepatitis requiring anti-HBV therapy and survived. One patient continued receiving acalarutinib. Among the patients with past HBV infection, 13 received ibrutinib and 1 (8%) had HBV reactivation; 14 received acalabrutinib and 1 (7%) had HBV reactivation (P=1.0). HBV reactivation risk is intermediate in patients with past HBV infection who receive BTK inhibitors. For patients with past HBV infection who received BTK inhibitors, data are insufficient to recommend universal anti-HBV prophylaxis, but monitoring for HBV reactivation is warranted.

Clinical Trials of Cellular Therapies in Solid Tumors.

In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials.

Lenalidomide overcomes the resistance to third-generation CD19-CAR-T cell therapy in preclinical models of diffuse large B-cell lymphoma.

Chimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors. In this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo. Lenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8+ CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment. In summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL.

Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies.

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.

CNS Aspergillosis Following BTK Inhibitors Mimicking Secondary CNS Lymphoma – A Case Series (P14-13.004)

<h3>Objective:</h3> NA <h3>Background:</h3> BTK inhibitors are commonly used in malignant B-cell lymphomas but can be associated with fungal infections, in part driven by altered platelet functions that diminish anti-fungal immune mechanisms. We describe four unique patients treated for B-cell malignancies (B-cell lymphoma, CLL, mantle cell lymphoma, and Waldenstrom’s disease) with progressive neurological deficits initially thought to represent secondary CNS lymphoma but on further diagnostic workup identified as CNS Aspergillosis. <h3>Design/Methods:</h3> Retrospective review of patients managed for B-cell hematological malignancies with BTK inhibitors associated with CNS Aspergillosis. <h3>Results:</h3> Four male patients (age 61–74) were treated with ibrutinib or zanubrutinib at a dose ranging from 160–560 mg daily (range 3–12 months) when developing new neurological symptoms and imaging findings were suggestive of recurrent lymphoma with CNS involvement. However, subsequent brain biopsies revealed invasive cerebral Aspergillosis in all cases with pulmonary involvement in three out of the four cases. Symptom presentation included headache and seizures (n=4), paresthesias (n=1) and expressive aphasia (n=1). Initial anti-fungal treatment consisted of voriconazole at a dose of 200–500 mg twice daily and subsequently posaconazole in three out of four patients. Additionally, three patients underwent surgical resection. Two patients remained stable without fungal disease progression for more than a year. One patient stopped taking voriconazole after 6 months due to side effects (decreased appetite, fatigue, lethargy, weight loss, and night sweats) and was eventually lost to follow-up. One patient had recurrent Aspergillosis and passed away following antifungal treatment for over two years. <h3>Conclusions:</h3> BTK inhibitors can be associated with fungal infections, including CNS involvement. These four cases illustrate the challenge in establishing a correct diagnosis and highlight the importance of considering atypical and fungal infections in individuals treated with BTK inhibitors. <b>Disclosure:</b> Ms. Murthy has nothing to disclose. The institution of Dr. Martinez-Lage has received research support from NIH. Jeremy Abramson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol-Myers Squibb. Jeremy Abramson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kite Pharma. Dr. Branagan has nothing to disclose. Dr. Ji has nothing to disclose. Yi-Bin Chen, 13609 has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Incyte. Yi-Bin Chen, 13609 has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Daiichi. Yi-Bin Chen, 13609 has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Equilium. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actinium. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celularity. Dr. Letourneau has received research support from World Health Information Science Consultants, LLC. Dr. Letourneau has received publishing royalties from a publication relating to health care. Brian Nahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Robeaute. Brian Nahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BK Ultrasound. Brian Nahed has stock in React Neuro. Brian Nahed has received research support from NIH. Dr. Nelson has nothing to disclose. Dr. Arrillaga-Romany has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boehringer Ingelheim. The institution of Dr. Arrillaga-Romany has received research support from Astex Pharmaceuticals. The institution of Dr. Arrillaga-Romany has received research support from Gsk. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Seattle Genetics. The institution of Dr. Wang has received research support from Merck. Dr. Wang has received publishing royalties from a publication relating to health care. Dr. Dietrich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Dietrich has received publishing royalties from a publication relating to health care.