CD19 Chimeric Antigen Receptor T-cell Research Articles

Comorbidities Associated with Early Mortality after CD19 CAR-T Cell Therapy

Objective: CD19 chimeric antigen receptor (CAR) T-cell therapy has changed the standard for treatment of relapsed and/or refractory (r/r) large b-cell lymphoma (LBCL). Currently, pre-treatment evaluation of patients and disease factors do not accurately predict outcomes. This study aims to identify risk factors associated with early mortality prior to day 100 after CAR-T infusion. Methods: We performed a single-centered retrospective adult patients (pts) with r/r LBCL who received CAR-T cell therapy between 2018-2021. CAR-T cell toxicities graded according to either CAR T-Cell Therapy-Associated Toxicity (CARTOX) grading system prior to May, 2019 or American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading thereafter for cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Comorbidities defined as per Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). (Sorror et al., 2009). Hepatic dysfunction defined as infection with hepatitis B or C or history of liver cirrhosis or elevated total bilirubin, AST, or ALT on at least two values on two different days from day -24 till day -10 prior to CAR-T. Cardiovascular (CV) comorbidity determined by presence of coronary heart disease, congestive heart failure or reduced ejection fraction detected by echocardiogram. Psychiatric disturbance defined as presence of depression and/or anxiety requiring treatment or consultation. Patient demographics, disease characteristics and clinical outcomes summarized through descriptive statistics. Wilcoxon rank sum test used to evaluate difference in a continuous variable between patient groups. Kaplan-Meier method used to estimate time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: Two hundred and fifty patients included in analysis. Median age of 61years (range: 18-89) and 30.8% of patients were female (n=77). Histology was categorized as LBCL (65.9%) and included diffuse LBCL or high grade LBCL, transformed follicular lymphoma (26.9%), primary mediastinal b-cell lymphoma (6.4%) or follicular lymphoma (0.8%). Majority of pts received axicabtagene ciloleucel 95.6% (n=239) while 4.4% (n=11) received tisagenlecleucel and 52% (n=130) of pts received bridging therapy. CRS of any grade was 90.4% ; ICANS any grade was 57.2% while grade 3 CRS/ICANS occurred 6.4% and 38.4% respectively. Median follow-up 24.7 months (mo) (95% CI: 20.7 ~ 26.4 mo). One-hundred twenty-eight pts died during follow-up, 48 pts died within 100 days, and most common cause of death was progression of lymphoma (29.2%; n=73). Early 30-day mortality occurred in 4.8% pts and causes of death due to CAR-T related toxicity in 6 pts, disease progression in 3 pts, and infection in 1 pts. 100-day mortality rate was 24.6% (n=32) for pts >60 years old vs 13.3% (n=16) for <60 (p-value=0.02). 100-day mortality rate was 36.5% for ECOG 2-4 vs 14.9% for ECOG 0-1 (p-value=0.0005). In terms of non-relapsed mortality (NRM), risk stratification according to cumulative HCT-CI score was not associated with higher 100-day NRM (p=0.24). Pts with cardiac score of 1 had a higher NRM (26.9% vs. 8.1%; p-value=0.005). The 100-day NRM rates for hepatic score of 0, 1, and 3 were 8.9%, 14.3%, and 50% (p-value=0.04). Pts with psychiatric disturbance score of 1 had higher 100-day NRM (19.6% vs. 7.8%; p-value=0.03). Conclusion: This single center retrospective study observed an increase in 100-day mortality in correlation with pre-treatment performance status, and older age. Pts with cardiac comorbidity, hepatic dysfunction or psychiatric disturbance had a higher 100-day NRM. Similar to other studies, the combined HCT-CI score was not predictive of NRM, but individual variables were associated with higher non-CART related toxicity. These findings require validation with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anti CD19 CAR-T Cell Therapy Can Clear Minimal Residual Disease in Bone Marrow of Patients with Relapsed or Refractory B Cell Non-Hodgkin's Lymphomas

Background: Anti CD19 Chimeric Antigen Receptor T (CAR-T) cell therapy is an effective treatment option for patients with relapsed/refractory B-cell lymphomas. There is limited data on the impact of CAR-T cell therapy on measurable residual disease (MRD) in the bone marrow of these patients. We hereby report CAR-T cell therapy's efficacy to treat bone marrow MRD in patient with relapsed/refractory B-cell lymphomas. Methods: In this retrospective review, patients receiving CAR-T cell therapy for relapsed/refractory B-cell lymphomas who had bone marrow MRD evaluation pre-and post-CAR-T infusion at the University of Arizona Cancer Center (UACC) were analyzed. MRD testing was performed via ClonoSEQ (Adaptive Biotechnologies) on bone marrow aspirates prior to CAR-T cell infusion. Patients with MRD+ (10^6) disease had serial MRD evaluations at day+30, +90, +180, +365 post CAR-T cell infusion. Results: Thirty-three patients with B-cell lymphomas received CAR-T cell therapy at UACC from January 2019 to July 2022. Bone marrow MRD pre-and post-CART was evaluated in ten patients. Baseline characteristics of these patients are outlined in Table 1. Seven (70%) were female, five (50%) had diffuse large B cell lymphoma (DLBCL), two (20%) patients had Richter's syndrome, two patients had transformed DLBCL from follicular lymphoma (FL), one patient had FL grade 3A. Nine (90%) patients were treated with Tisagenlecleucel and one (10%) patient received Axicabtagene ciloleucel CAR-T product. Of the ten patients who had MRD testing done pre-and post-CAR-T, seven (70%) had MRD positive disease prior to treatment. Five of the seven patients converted to MRD negative 10^6 post-CAR-T cell infusion. One patient tested MRD positive below the level of detection on day +30 bone marrow aspirate. One patient is still MRD positive 6 months post-CAR-T infusion but the depth of response continues to improve from MRD positive at 10^4 to MRD negative at 10^5, 6 months post-CAR-T infusion. All MRD positive patients achieved complete metabolic response (CMR) based on the positron emission tomography scans. Conclusion: CAR-T cell therapy has the potential to treat minimal residual disease in patients with B-cell lymphoma. Depth of bone marrow response continues to improve over time. All patients continue to be in CMR. Long term follow-up will help determine if persistent MRD can be used as prognostic marker in B cell lymphomas post CAR-T cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eltrombopag Stimulation for Neutrophil and Platelet Recovery Following Axicabtagene Ciloleucel (axi-cel) Therapy in Lymphoma

Introduction: Prolonged cytopenia is a potential side effect of CD-19 chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma. ZUMA-1 demonstrated around 20% of axicabtagene ciloleucel (axi-cel) recipients had prolonged cytopenia at 3 months. Grade 3-4 cytopenia was observed in 11% of patients (Pts) at 2 years. While the mechanism behind the prolonged cytopenia is not yet well understood, one management strategy is to stimulate the bone marrow with the thrombopoietin receptor agonist, eltrombopag. This strategy is widely used in diseases like aplastic anemia and immune-mediated thrombocytopenia, but there has been limited evidence surrounding its use with cytopenia following CAR-T. Our practice is to utilize eltrombopag starting at Day 30 following CAR-T administration if either absolute neutrophil count (ANC) < 1000 cells/µL and/or if a patient is requiring growth factor support, and/or if a patient has thrombocytopenia, defined as a platelet count less than 20,000 cells/µL and/or if a patient is dependent on platelet transfusions at Day 30. We compared count recovery, progression-free survival (PFS), and overall survival (OS) of axi-cel recipients who required eltrombopag and those who did not. Methods: A retrospective cohort of 50 adult pts treated at the University of Kansas Cancer Center who had previously received axi-cel for B-cell non-Hodgkin lymphoma between 2018-2021 were reviewed for clinical endpoints in this study. The patients were stratified into two groups based on whether they had received eltrombopag for count recovery following CAR-T administration. Pts whose disease progressed were censored at the time of progression in the analysis of outcomes. Count recovery was measured based on recovery past the lower limit of normal at our institutional lab, ANC less than 1.8 K/µL, and platelets less than 150 K/µL. Results: Twenty (40%) pts received eltrombopag.Demographics were compared between the two groups as shown in Table 1. Patients who received eltrombopag had significantly lower platelet and ANC counts (p= 0.03 and 0.01 respectively). Those who received eltrombopag had a significantly higher incidence of bone marrow involvement at the time of axi-cel administration (p=0.002). The median duration of eltrombopag was 115 Days (9-524 days). The eltrombopag cohort continued to have significantly lower platelet (120 vs 183 K/µL, p=0.02) and ANC (1.95 vs 3.07 cells/µL, p=0.01) at 1 year. No statistically significant difference was observed in PFS or OS between patients who had received eltrombopag and those who did not, with a combined PFS of 16.5 months (p=0.54) (Figure 1) and a combined OS of 26 months (p=0.95). Conclusion: We conclude that patients on eltrombopag had significantly lower ANC and platelet counts even at 1-year post-CAR-T. The eltrombopag group had similar OS and PFS to those who the group without cytopenia. The role of eltrombopag in the patients with prolonged cytopenia is not entirely clear and warrants further investigation, especially considering the cost of administration and risk of secondary myelodysplasia (MDS). Larger multi-center retrospective studies and prospective data of the role of eltrombopag in improving outcomes are needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Race and Social Determinants of Health on Outcomes in Patients with Aggressive B-Cell Lymphomas Treated with Chimeric Antigen Receptor T-Cell (CART) Therapy

Background: Health care disparities, driven by multiple social, economic, and/or environmental factors lead to inequalities in health outcomes. With CAR T-cell therapy (CART), differences in response rates have been identified across race. However, data that address the convergence of race with other social determinants of health on outcomes with CART remain limited. We examined the impact of interactions between race, insurance status, clinical trial utilization, and age on access to care and outcomes in patients (pts) treated with CART for aggressive B-cell lymphomas (B-NHL). Methods: Adult pts with relapsed/refractory B-NHL treated with CD19 CART between 2015- 2021 across 13 US academic centers were identified. Insurance type, demographic and clinical data were collected and analyzed via Chi-squared and Kaplan-Meier analysis. Cox multivariable regression was used to determine impact of race/ethnicity and other variables on survival. Variables used in the multivariable analysis (MVA) included race, age, insurance type, prior autologous stem cell transplantation (autoSCT), CART on clinical trial, use of bridging therapy, IPI at CART infusion, and elevated LDH pre-CART. Race (Caucasian, African American (AA), Asian or Other with the latter cohort excluded from analyses) and ethnicity (Hispanic vs non-Hispanic) were self-reported by pts. Results: A total of 466 adult pts were included. Table 1 outlines demographic, clinical, and health care utilization parameters by race. 406 (87%) were Caucasian, 34 (7%) AA and 26 (6%) Asian; 9 (2%) were Hispanic (all Caucasian). Caucasians were older compared to AAs and Asians (median age 59 vs 55 vs 55 yrs; p=0.004). Median number of lines of therapy prior to CART were similar across race (p=0.44). Caucasians were more likely to have a prior autoSCT (p= 0.04). For Caucasians vs AAs vs Asians: rates of bridging were 44% vs 61% vs 46% (p=0.17) and rates of utilization of clinical trials for CART access were 29% vs 15% vs 19% (p=0.12), respectively. Median time from last relapse/progression pre-CART to CART was 2 vs 1.8 vs 1.2 mo (p=0.9) and median time from apheresis to CART was 1.1 vs 1.1 vs 0.9 mo (p=0.2), respectively. D180 ORR were 51% vs 46% vs 19% (p =0.01) with D180 CR rates of 43% vs 42% vs 19% (p = 0.17), respectively. No difference in grade >/= 3 CRS or ICANS was observed across race. Median follow-up after CART was 12.7 mo. Median PFS (mPFS) was longer for Caucasians (11.5 mo) than for AAs (3.5 mo, HR 1.56 [1.03-2.4], p=0.04) or Asians (2.7 mo, HR 1.7 [1.02-2.67], p=0.04). Differences in median OS (mOS) were not statistically different: mOS was 25.4 mo in Caucasians vs 30.4 mo in AAs (HR 1.0 [0.59 - 1.69], p=0.99) vs 16.8 mo in Asians (HR 1.42 [0.84 - 2.42], p=0.19). Rates for administration of therapy after CART failure were non-significantly higher for Caucasians vs AAs or Asians, (46% vs 25% vs 28%, p = 0.05). On MVA, race, insurance type, use of bridging, and elevated LDH pre-CART impacted PFS (p < 0.001 - 0.031, Table 2). As compared to Caucasians, AAs (but not Asians) had a worse PFS (HR 1.72 [1.05 - 2.82], p = 0.03). Race did not impact OS. Medicare, lack of bridging, and receipt of further therapy post CART failure positively impacted OS (p = 0.006 - 0.044). Insurance type did not impact median time from last relapse/progression to CART. However, there were significant differences in mPFS and mOS between payer groups: mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 mo (p<0.001) and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 mo (p<0.001) for Medicare (n=206) vs Medicaid (n=33) vs private insurance (n=219) vs self-pay (n=7). Conclusion: In our cohort, AAs and Hispanics were greatly underrepresented which underscores the presence of health care disparities across race and ethnicity for relapsed/refractory B-NHL. With CART, Caucasians had similar complete response rates but longer mPFS as compared to AAs and Asians warranting exploration of factors that may predict for early progression in racial minorities. No difference in OS was observed by race perhaps attributed to the effects of next line therapy after CART. Insurance type impacted both PFS and OS with best outcomes seen in pts with Medicare. Results do not capture pts facing insurance denial and/or poor access that would likely augment trends for race and socioeconomic disparities identified in our CART population. The interaction between race and insurance status and their relative contributions to access and outcomes with CART should be further explored. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Body Composition and Immunonutritional Status Impact Survival Outcomes after CD19 CAR T-Cell Therapy

Introduction: While CD19 chimeric antigen receptor T-cell therapy (CD19.CART) has altered the treatment landscape for multiple relapsed/refractory (r/r) B-cell malignancies, over 50% of patients ultimately relapse. To elucidate relapse mechanisms, previous studies have predominantly focused on disease- and treatment-related risk factors, while few studies have looked at systemic, host-intrinsic features. In this context, we recently demonstrated that an increase of metabolically high-risk adipose tissue sites, particularly visceral fat, impacts cytokine release syndrome onset and severity via IL-6 (Dos Santos & Rejeski et al, Haematologica 2022). We therefore hypothesized that body composition and nutritional status may also affect post-CAR-T survival outcomes. Methods: In this single-center, retrospective observational analysis, we studied patients receiving CD19.CAR-T for r/r B-cell malignancies between 01/2019 and 03/2022 in a real-world setting. We comprehensively analyzed the impact of immunometabolic host features including body composition (BC) measurements on clinical outcomes. We extracted psoas and skeletal muscle indices (PMI/SMI) as well as subcutaneous, visceral and epicardial adipose tissue (SAT/VAT/EAT) distributions from pre-lymphodepletion CT images. We further assessed the laboratory-based immuno-nutritional scores Glasgow Prognostic Score (GPS), CRP/Albumin Ratio and the Prognostic Nutritional Index (PNI). Efficacy outcomes were assessed according to Lugano criteria for B-NHL (LBCL, MCL) and according to MRD status for BCP-ALL. Durable responders were defined as reaching at least a partial remission (PR) or better by day 90, while non-responders had stable disease (SD), progressive disease (PD), or died due to treatment-related causes. Results: 66 consecutively treated patients were included in this analysis (53 LBCL, 9 MCL, 4 BCP-ALL). The following CD19.CART products were applied: axi-cel in 22 patients, tisa-cel in 25 patients and brexu-cel in 9 patients. Patients received a median of four prior treatment lines, which included a stem cell transplantation in 24 patients. The best 90-day overall response rate was 51.5%, with a complete remission rate of 40.9%. At a median follow-up time of 19 months, median PFS was 3.2 months and median OS 14 months. Based on the BC analysis, we found that CAR-responders displayed increased visceral adipose tissue deposits compared to CAR-non-responders (VAT: 120 vs. 67 cm2, p=0.01). Furthermore, immuno-nutritional scores (GPS, CRP/Albumin-Ratio, PNI) were significantly altered in non-responding patients. Next, we defined cut-off values for further analyses based on receiver operating characteristics for adipose tissue parameters and immunonutritional scores, and on optimal log-rank test separation for sarcopenia parameters. On univariate cox regression analysis, patients with VAT > 61.8 cm² exhibited a significantly lower risk of poor OS (Hazard Ratio [HR] = 0.35, 95% CI 0.18-0.70). Concomitantly, median PFS (5.1 vs. 1.9 months, p=0.04) and median OS (not-reached vs. 2.9 months, Fig. 1A) were significantly extended in patients with excess visceral adipose tissue. On the other hand, a SMI < 34.5 cm²/m², an indicator for sarcopenia, was associated with inferior OS (median 2.4 vs. 16.8 months, Fig. 1B). In a multivariate analysis adjusting for baseline CRP, LDH and ECOG performance status, increased VAT > 61.8 cm² was associated with improved clinical outcomes (high VAT: adjusted HROS: 0.28, 95% CI 0.13-0.59, p=<0.001). Conversely, sarcopenia significantly increased the risk of poor survival (low SMI: aHROS: 3.63, 95% CI 1.47-8.99, p=0.005). Moreover, malnutrition, defined by a PNI < 39.7, was associated with worse PFS and OS (low PNI: aHROS: 3.27, 95% CI 1.38-7.77, p=0.007). Conclusions: These findings highlight that body composition and nutritional status play a role as host-intrinsic prognostic factors in the context of CD19.CART. The link between visceral adipose tissue and improved survival suggests that the obesity paradox may extend to patients receiving T-cell based immunotherapies. If validated in future prospective studies, data on body composition and nutritional status may complement existing risk-stratification tools for patients receiving CD19-CART, and may lead to exercise- and diet-based interventional strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exploring the mechanisms of CD19 CAR T-cell failure and salvage strategies in B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential treatment for patients with B-cell lymphoma in whom standard therapy has failed. The U.S. Food and Drug Administration (FDA) has approved anti-CD19 CAR T-cell products for B-cell lymphoma. However, growing experience has shown that treatment has limitations, such as relapses due to tumour mutations or CD19 antigen loss, unexpanded CAR T-cells, and/or poor persistence of CAR T-cells. Understanding the limitations of CAR T-cell therapy is essential to achieve the full potential of this therapeutic strategy. In this review, we analyse factors potentially affecting the efficacy of CAR T-cell therapy, explore the mechanisms of resistance to CD19 CAR T-cell therapy in B-cell lymphoma, and summarise potential strategies to overcome treatment barriers.

Comprehensive Salvage Radiotherapy for Limited Relapsed B-Cell Non-Hodgkin Lymphoma Following CD19 Chimeric Antigen Receptor T-Cell Therapy

<h3>Purpose/Objective(s)</h3> Significant relapse rates following CD19 Chimeric Antigen Receptor T-Cell Therapy (CART) for relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) remain a challenge. This study aims to better define the role of salvage radiotherapy (SRT) after CART. <h3>Materials/Methods</h3> We retrospectively reviewed 48 patients with r/r aggressive B-cell NHL who received SRT following CART from 2018 to 2021. SRT local control rate (LC) - calculated based on the total number of irradiated sites, freedom from subsequent progression (FFSP), freedom from subsequent event (FFSE) – accounting for subsequent progressions and salvage therapies, and overall survival (OS) were defined from SRT start date. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. SRT was defined as comprehensive (compSRT) – treated all sites of active disease – or focal (focSRT). Limited disease was defined as disease amenable to comprehensive RT, either as localized (encompassable in one RT field) or oligo-diffuse (≤4 sites). Kaplan-Meier plots and Cox regression modeling were used to estimate the desired output. <h3>Results</h3> Median age of the cohort at time of CART infusion was 58 (range 19-73) years, and median time from CART infusion to SRT was 103 (range: 23-842) days. The median equivalent 2 Gy dose (EQD2) was 37.4 Gy (range 4-52 Gy) for compSRT and 24.2 Gy (range 4.7-48.8) for focSRT. The most common regimens were 36 Gy in 12 fractions in compSRT and 20 Gy in 5 fractions in focSRT. A total of 65 sites treated in 37 patients had adequate imaging follow-up after SRT. Of the irradiated sites, 21 lesions (32%) in 16 patients experienced in-field recurrence, translating to 1-year LC of 62%. No in-field recurrence occurred beyond 210 days. On univariate analysis, tumor size, SUVmax, and LDH >2x upper limit (UL) at the time of SRT were significantly associated with increased risk of in-field recurrence. On the multivariate analysis, LDH >2x UL (OR 6.5, CI: 1.8-24.3; p=0.005) and SUVmax (OR 1.06, CI: 1.002-1.12; p=0.044) retained significant association with in-field recurrence. There were 37 patients with limited disease and 11 with extensive disease and the 1-year OS was 39% and 0% (p<0.001), respectively. Among those with limited disease, 26 received compSRT and 11 received focSRT. At a median follow-up period of 20 months, patients with limited disease who received compSRT had significantly higher 1-year FFSP (31% vs. 0%; p<0.001), 1-year FFSE (19% vs. 0%; p=0.01), and 1-year OS (51% vs. 12%; p=0.028) compared to focSRT. <h3>Conclusion</h3> Post-CART compSRT for r/r B-cell NHL is a reasonable salvage intervention for patients with limited relapsed disease and is associated with better FFSP, FFSE and OS compared to focSRT. Patients who have elevated LDH >2 x UL and high SUVmax prior to SRT are likely at the highest risk of in-field recurrence and may benefit from escalation of therapy.

ABCL-088 Subgroup Analysis in RE-MIND2: An Observational, Retrospective Cohort Study of Tafasitamab + Lenalidomide Versus Systemic Therapies in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Tafasitamab+lenalidomide (LEN), a chemo-free immunotherapy for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), demonstrated efficacy in autologous stem cell transplant-ineligible patients in the single-arm L-MIND study (NCT02399085). RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient cohorts treated with other systemic therapies. Prolonged overall survival (OS) with tafasitamab+LEN was detected compared to a cohort of pooled systemic therapies (PST), bendamustine+rituximab (BR), rituximab+gemcitabine+oxaliplatin, polatuzumab vedotin+BR (pola-BR), and rituximab+LEN (R2). Comparable OS was detected versus CD19 chimeric antigen receptor T-cell therapies (CAR-T). However, limited information is available on the comparative effectiveness of tafasitamab+LEN in specific subpopulations. This study aimed to determine the relative effectiveness of tafasitamab+LEN versus other treatments for R/R DLBCL in clinically relevant patient subgroups in the absence of head-to-head trials. The L-MIND cohort was matched with RE-MIND2 patients using estimated propensity score-based 1:1 nearest neighbor matching balanced for a minimum of six covariates. Sensitivity analyses were conducted. The study was conducted at academic, public, and private hospitals in Europe, North America, and the Asia-Pacific region. Patients were ≥18 years old with histologically confirmed DLBCL and ≥2 prior systemic therapies for DLBCL, including ≥1 anti-CD20 therapy. Data are presented for tafasitamab+LEN versus PST, versus pola-BR, versus R2, and versus CAR-T. Hypothesis-generating analyses were conducted for patient subgroups of number of extranodal sites (ENS) (0-1 vs. ≥2) and elevated lactate dehydrogenase (LDH) (yes vs. no). The primary endpoint was OS. Of 3,454 patients enrolled, 961, 106, 106, and 149 were treated with PST, pola-BR, R2, and CAR-T, resulting in 76, 24, 33, and 37 matched pairs for patients receiving tafasitamab+LEN, respectively. Hazard ratios for OS for patients with ≥2 ENS were 0.803, 0.524, 0.478, and 1.459, and for patients with elevated LDH were 0.627, 0.585, 0.420, and 1.663, for comparisons of tafasitamab+LEN versus PST, pola-BR, R2, and CAR-T, respectively. There was a trend towards favoring tafasitamab+LEN in most patient subgroups. The combination may be associated with improved OS versus selected systemic therapies for certain patients with high-risk disease. These analyses are not powered for statistical comparison and should be interpreted with caution. Funding: MorphoSys AG.

Gene Therapy Hits Its Stride in the Clinic

Gene Therapy Hits Its Stride in the Clinic

Microraft arrays for serial-killer CD19 chimeric antigen receptor T cells and single cell isolation.

Chimeric antigen receptor T (CAR-T) cell immunotherapies have seen success in treating hematological malignancies in recent years; however, the results can be highly variable. Single cell heterogeneity plays a key role in the variable efficacy of CAR-T cell treatments yet is largely unexplored. A major challenge is to understand the killing behavior and phenotype of individual CAR-T cells, which are able to serially kill targets. Thus, a platform capable of measuring time-dependent CAR-T cell mediated killing and then isolating single cells for downstream assays would be invaluable in characterizing CAR-T cells. An automated microraft array platform was designed to track CD19 CAR-T cell killing of CD19+ target cells and CAR-T cell motility over time followed by CAR-T cell collection based on killing behavior. The platform demonstrated automated CAR-T cell counting with up to 98% specificity and 96% sensitivity, and single cells were isolated with 89% efficiency. On average, 2.3% of single CAR-T cells were shown to participate in serial-killing of target cells, killing a maximum of three target cells in a 6h period. The cytotoxicity and motility of >7000 individual CAR-T cells was tracked across four microraft arrays. The automated microraft array platform measured temporal cell-mediated cytotoxicity, CAR-T cell motility, CAR-T cell death, and CAR-T cell to target cell distances, followed by the capability to sort any desired CAR-T cell. The pipeline has the potential to further our understanding of T cell-based cancer immunotherapies and improve cell-therapy products for better patient outcomes.

Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy.

CD19-targeted chimeric antigen receptor (CAR) T-cell becomes a breakthrough therapy providing excellent remission rates and durable disease control for patients with relapsed/refractory (R/R) hematologic malignancies. However, CAR T-cells have several potential side effects including cytokine release syndrome, neurotoxicities, cytopenia, and hypogammaglobulinemia. Infection has been increasingly recognized as a complication of CAR T-cell therapy. Several factors predispose CAR T-cell recipients to infection. Fortunately, although studies show a high incidence of infection post-CAR T-cells, most infections are manageable. In contrast to patients who undergo hematopoietic stem cell transplant, less is known about post-CAR T-cell immune reconstitution. Therefore, evidence regarding antimicrobial prophylaxis and vaccination strategies in these patients is more limited. As CAR T-cell therapy becomes the standard treatment for R/R B lymphoid malignancies, we should expect a larger impact of infections in these patients and the need for increased clinical attention. Studies exploring infection and immune reconstitution after CAR T-cell therapy are clinically relevant and will provide us with a better understanding of the dynamics of immune function after CAR T-cell therapy including insights into appropriate strategies for prophylaxis and treatment of infections in these patients. In this review, we describe infections in recipients of CAR T-cells, and discuss risk factors and potential mitigation strategies.

Low incidence of invasive fungal disease following CD19 chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma

AbstractCAR T-cell therapy has revolutionized the treatment of hematologic malignancies, although its use may be complicated by toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Invasive fungal disease (IFD) has been reported after CAR T-cell therapy, but the incidence in the absence of antifungal prophylaxis is unknown. Optimal prophylaxis strategies are widely debated. We performed a single-center retrospective study of 280 adults receiving CD19 CAR T-cell therapy for non-Hodgkin lymphoma (NHL) from December 2017 through September 2021. Patients did not receive routine antiyeast or antimold prophylaxis. IFD was identified between day of cell infusion and last follow-up. Cumulative incidence functions were calculated at 100 days and 18 months based on time to IFD, using dates of IFD-free death, initiation of salvage treatment, and hematopoietic cell transplantation as competing risks. Eight patients (2.9%) developed IFD, including 3 Pneumocystis jirovecii pneumonia, 3 invasive mold infections (IMIs), and 2 invasive yeast infections (IYIs). The 100-day cumulative incidence of IFD accounting for competing risks was 1.8% (95% confidence interval [CI], 0.8% to 4.4%). Among the 280 patients, early toxicities including CRS (85%) and ICANS (55%) and late toxicities after day 30 including grades 3 and 4 neutropenia (41%) and low CD4 T-cell count (20%) were common. IFD was rare among patients who received CD19 CAR T-cell therapy for NHL in the absence of routine antifungal prophylaxis, despite frequent toxicities. These results suggest that, in settings with low institutional rates of IFD, routine antifungal prophylaxis may not be indicated.

P1197: AXICABTAGENE CILOLEUCEL (AXI-CEL) IN COMBINATION WITH RITUXIMAB FOR THE TREATMENT OF RELAPSED/REFRACTORY (R/R) LARGE B-CELL LYMPHOMA (LBCL): OUTCOMES OF THE PHASE 2 ZUMA-14 STUDY

Background: Despite the success of axi-cel, ≈60% of patients have no response or relapse within ~2 y after treatment (Jacobson C, et al. ASH 2021. #1764), highlighting the need for more therapeutic strategies. In preclinical studies, rituximab augmented CD19 chimeric antigen receptor (CAR) T-cell function and increased tumor reduction and survival in murine models via synergistic targeting with CAR T-cells (Mihara K, et al. Br J Haematol. 2010). Aims: Here, we report outcomes of ZUMA-14, a Phase 2, multicenter study of axi-cel in combination with rituximab in pts with R/R LBCL after ≥2 lines of systemic therapy. Methods: Eligible patients were ≥18 y with R/R LBCL. Patients received one rituximab dose (375 mg/m2) on Day -5, a conditioning regimen of cyclophosphamide and fludarabine on Days -5, -4, and -3, and a single axi-cel infusion of 2×106 CAR T cells/kg on Day 0. Starting on Day 21 post–axi-cel infusion, patients received 1 rituximab dose every 28 days for up to 5 doses. The primary endpoint was investigator-assessed complete response (CR) rate. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and biomarker assessments. The analysis reported here occurred after all treated patients had ≥12 months of follow-up. Results: As of 12/2/21, 27 patients were enrolled, and 26 received axi-cel and ≥1 rituximab dose (15 patients received all 6 rituximab doses); 1 patient discontinued treatment due to an adverse event (AE). Median age was 63 y (range, 38-82), 54% were male, 81% had stage III/IV disease, 62% had extranodal disease, 38% had elevated lactate dehydrogenase, and 85% had an age-adjusted International Prognostic Index (aaIPI) ≥1 (35% aaIPI=2). The CR rate was 65% (95% CI, 44%-83%), and the ORR was 88% (95% CI, 70%-98%). With a median follow-up of 17 months, 65% of the patients had ongoing response, with 57% ongoing in CR. Medians for DOR, PFS and OS were not reached. The estimated DOR and PFS rates at 12 months were 64% and 56%, respectively. The estimated 12-month OS rate was 76%, and 6 patients (23%) died of progressive disease. Most patients (92%) experienced Grade ≥3 AEs. Grade ≥3 cytopenias were reported in 85% of patients, with 38% ongoing on Day 30. Grade ≥3 neurologic events (NEs) occurred in 4 patients (15%); there was no Grade ≥3 cytokine release syndrome (CRS). Median times to onset of CRS and NEs were 4 days (range, 1-7 days) and 6 days (range, 3-32 days), respectively, with median durations of 5 days (range, 2-15 days) and 7 days (range, 1-39 days). No patients experienced myelodysplastic syndrome. Median peak CAR T-cell levels were comparable to the ZUMA-1 pharmacokinetic profile. Immune-modulating cytokines, including granzyme B, IL-6, CXCL10, IFN-γ and IL-2, were induced in patients following axi-cel and rituximab infusion and were more prominently elevated in responders vs non-responders. Peak rituximab levels were also elevated in responders vs non-responders. Summary/Conclusion: Results from ZUMA-14 demonstrated that axi-cel in combination with rituximab elicited a high CR rate and durable PFS with no new safety signals detected in patients with R/R LBCL.

Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for B-cell acute lymphoblastic leukemia (B-ALL). Although allo-HSCT can be curative for some B-ALL patients, relapse still occurs in some patients following allo-HSCT. Conventional chemotherapies show poor efficacy in B-ALL patients who have relapsed following allo-HSCT. In the past decade, chimeric antigen receptor T-cell (CAR-T) therapy has shown to be efficacious for B-ALL patients. In particular, autologous CD19 CAR-T therapy results in a high remission rate. However, there are challenges in the use of CD19 CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, including the selection of CAR-T cell source for manufacturing, post-CAR-T graft-versus-host disease (GVHD) risk, maintenance of long-term efficacy after remission through CAR-T therapy, and whether a consolidative second transplant is needed. In this review, we describe the current status of CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, the advantages and disadvantages of various CAR-T cell sources, the characteristics and management of GVHD following CAR-T therapy, and the risk factors that may affect long-term efficacy.

S207: EFFICACY AND SAFETY OF A THIRD GENERATION CD20 CART (MB-106) FOR TREATMENT OF RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA (FL)

Background: Follicular lymphoma (FL) is incurable and novel treatments with high efficacy and low toxicity are needed. Chimeric antigen receptor T-cells (CAR-T) targeting CD19 are effective, and axicabtagene ciloleucel is currently approved by FDA for treatment of patients (pts) with relapsed FL, but toxicities like cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may limit its use. MB-106 is a fully human 3rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains. Aims: We present the results of the FL cohort from our ongoing phase I/II clinical trial investigating MB-106 for B-cell lymphoma/CLL. Methods: Pts with R/R B-cell malignancies including FL were eligible after confirmation of CD20 expression. Prior treatment with CD19 CAR-T is permitted. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. A continual reassessment method dose escalation design was used to find the maximally tolerated dose. CAR-T was infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Initial treatment response is assessed on day 28 and best response is reported here. CRS and ICANS are graded per ASTCT. Results: Between Dec 2019 and Dec 2021, 16 pts with FL were treated and had day 28 assessment. Median age was 61.5 years (range: 45 – 81). High-risk features included pts with progression of disease within 24 months of first-line chemotherapy (POD24) (n=11; 69%), history of histologic transformation (n=3; 19%), prior treatment with a CD19 targeted CAR-T (n=1; 6%). 6 pts (37.5%) had a PI3 kinase inhibitor. Median time between leukapheresis and LD was 15 days (range: 9-21) and 2 pts received bridging therapy with lenalidomide (1) and high-dose corticosteroids (1). All DLs were reached (DL0=1, DL1=1, DL2=4, DL3=7, DL4=2), with no dose-limiting toxicities. All CRS events were grade 1 (n=4; 25%) or grade 2 (n=1; 6%), with no grade ≥ 3 CRS events. There was no occurrence of ICANS of any grade. No pts had tumor lysis syndrome or Gr 3-4 infections. In the first 28 days, thrombocytopenia (Gr 3-4: 12.5%) and neutropenia (Gr 3-4: 94%) were common but there were no bleeding complications, and the rate of febrile neutropenia was 25%. Overall response (ORR) rate was 94% (15/16) and a complete response (CR) rate was 75% (12/16). Pts who received DL3 or DL4, had an ORR 100% and CR rate of 89%. The single patient who had previously been treated with a CD19 targeted CAR-T achieved a CR. With median follow-up of 10 months, one patient died, from complications of myelodysplastic syndrome (MDS) while still in remission; the MDS was attributed to the prior treatments (7 lines of chemo-based therapy and radioimmunotherapy). Most of the remissions are ongoing and 4 pts have relapsed during the follow-up median 7 months after treatment (range 3-10.5). CAR T cells were detectable by flow cytometry at last available timepoint (up to 2 years) for 15 of 16 patients. One patient had undetectable CAR T cells by day 201. Summary/Conclusion: Treatment with MB-106, a third generation CD20 targeting CAR-T, resulted in high ORR and CR rates and CAR-T persistence in FL pts and was associated with favorable safety profile with no occurrence of Gr 3 or Gr 4 CRS and no ICANS event of any grade. A multicenter trial for treatment of B-cell malignancies including FL will start enrollment in 2022.

Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience.

Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50mg/day and gradually increased to a maximal dose of 150mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.

Cost-effectiveness of CD19 chimeric antigen receptor T-cell (CAR-T) therapy versus autologous stem cell transplantation (ASCT) for high-risk diffuse large B-cell lymphoma (DLBCL) in first relapse.

7537 Background: The recently reported ZUMA-7 and TRANSFORM trials demonstrate superior event-free survival among patients with primary refractory or early relapsed DLBCL compared to salvage chemotherapy with ASCT. However, given a cost of &gt;$370,000, it is not known whether second-line CAR-T is cost-effective compared to ASCT. Thus, we developed a state-transition microsimulation model to simulate clinical outcomes and costs associated with therapy for DLBCL patients in first relapse, using ZUMA-7 and TRANSFORM data. Methods: The model begins at initiation of second-line therapy comparing salvage chemotherapy with ASCT or CAR-T therapy. We examined a three-year time horizon, including crossover to the alternative strategy therapy in the third line, as well as subsequent lines of therapy, using open-source Amua 0.3.0 software. Base case analysis was performed using 1000 first-order Monte Carlo simulations and probabilistic sensitivity analysis (PSA) was performed with 1000 simulations to test model uncertainty. Conditional probabilities of survival and disease progression were extracted from Kaplan-Meier curves from pivotal clinical trials using the WebPlotDigitizer tool. Costs were estimated from public sources in US Dollars ($) and effects were estimated in quality-adjusted life years (QALY) using published utility values. Results: Median overall survival was 15 months (95% confidence interval [CI] 13-19 months) with ASCT and 21 months (95% CI 17-29 months) with CAR-T. The PSA demonstrated costs and effectiveness per patient of $243,581 and 1.06 QALYs with ASCT and $470,150 and 1.22 QALYs with CAR-T with an incremental cost-effectiveness ratio (ICER) of $1,383,320/QALY. Incremental net monetary benefit of CAR-T versus ASCT, based on a willingness-to-pay (WTP) threshold of $200,000/QALY, was -$193,812. The break-even price for CAR-T and all subsequent therapies, based on a one-way sensitivity analysis, was $170,489. Conclusions: The model demonstrated improved survival and QALYs for the second-line CAR-T therapy, but was not cost-effective, as the ICER exceeded $1,000,000/QALY, which is higher than most accepted WTP thresholds. A limitation of these early data is that they only assess outcomes over three years. To estimate the full effect of these therapies, we will extrapolate the Kaplan-Meier curves for additional analyses. Clinical outcomes of second-line CAR-T are promising, but prices would need to be considerably lower to enable equitable access and affordability.[Table: see text]

In-field recurrences in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) bridged with radiation prior to CD19 chimeric antigen receptor T-cell therapy (CART).

7556 Background: The majority of R/R NHL progressions after CART involve pre-existing sites, suggesting a promising role for bridging radiotherapy (bRT). We assessed the local control rate of disease sites bridged with radiotherapy prior to CART and identified predictors of in-field recurrence. Methods: We retrospectively reviewed 35 patients with aggressive B-cell NHL who received bRT between leukapheresis and CART infusion between 2018 and 2021 at a multi-site single institution. bRT local control rate (LC), calculated based on the total number of irradiated sites, was defined from bRT end date. Progression-free survival (PFS) and overall-survival (OS) were defined from the date of CART infusion. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. Kaplan-Meier plots and cox regression modeling were used to estimate the desired output. Results: Median age of the cohort at time of CART infusion was 59 (range 19-73). The median equivalent 2 Gy dose (EQD2) administered was 23.3 Gy (range 4-41 Gy). The median time from end of bRT to CART infusion was 14 days (range 6-42). Five (14%) patients also received bridging chemotherapy with bRT. Among the 34 evaluable patients, 30 (88%) achieved an objective response (59% complete response and 29% partial response). At a median follow-up of 12 months, 1-year PFS was 48% and 1-year OS was 72%. No progression occurred beyond 240 days. On review of treatment plans and pre-treatment PET/CT scans, 59 sites were identified that received bRT prior to CART infusion. The median size and SUVmax of the irradiated sites were 8.7cm (range 1.5-22) and 13 (range 4-46), respectively. Of the 59 irradiated sites, 8 sites (13.6%) in 7 patients had in-field local recurrence, translating to 1-year LC of 84%. No in-field recurrence occurred beyond 180 days. Moreover, no local recurrence occurred in patients who received radiation to all known sites of active disease to EQD2&gt; 30 Gy (n = 4 patients); these patients remained in remission except for 1 who experienced progression outside the bRT field. On univariate analysis, triple hit lymphoma (THL) (OR 22.8, 95% CI: 3.8-138.3; p &lt; 0.001), tumor size (OR 1.25, 95% CI: 1.1-1.4; p &lt; 0.001), specifically ≥ 9cm (OR 9.4, CI: 1.2-77.3; p = 0.036) and SUVmax (OR 1.1, CI: 1.02-1.15; p = 0.008), specifically ≥ 20 (OR 5.6, CI: 1.3-23.7; p = 0.018), were significantly associated with increased risk of in-field recurrence. On multivariate analysis, THL (OR 32.9, CI: 3.2-336.0; p = 0.03) and tumor size (OR 1.3, CI: 1.1-1.6; p = 0.01) retained significant association with in-field recurrence. Conclusions: Bridging radiotherapy prior to CART provides excellent and durable in-field local control for R/R B-cell NHL. Patients with triple hit histology and bulky disease are likely at higher risk of in-field recurrence and may benefit from higher doses of bRT.

Special issue: CAR‐T cell therapy for hematological malignancies

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of relapsed/refractory (R/R) B-cell derived hematological malignancies, including acute lymphoblastic leukemia (ALL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM). CD19-targeted CAR-T cells yield complete remission (CR) rates of about 90% in R/R ALL and about 50% in R/R NHL, respectively, while BCMA-targeted CAR-T cells yield CR rate of about 50%−80% in R/R MM. Notably, the US Food and Drug Administration have approved six CAR-T cell products (tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel) for the treatment of R/R B-NHL, R/R ALL, and R/R MM. However, some patients might not respond to such therapy or quickly relapse after CAR-T cell infusion, which is likely due to the dysfunction and poor persistence of CAR-T cells or the modulation of specific antigen. Thus, alternative treatment strategies must be investigated. In addition, accumulating research have been conducted to discover novel target of antigens with therapeutic efficacy and utility for generating CAR-T cells against acute myeloid leukemia (AML). Safety during CAR-T cell treatment is another important issue, concerning complications such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), pancytopenia, and infection. Despite the fact that the majority of those adverse effects are minimal, the risk of a life-threatening situation still exists. Cautious treatment for severe adverse events requires a multidisciplinary approach with involvement of not only oncologists but also other internal medicine doctors to guarantee diagnosis and treatment in time. Therefore, it is of vital importance to understand the novel advances of CAR-T cell therapy. This special issue of ImmunoMedicine focuses on novel developments of CAR-T cell therapy for hematological malignancies. The review from Xiangmin Wang (https://doi.org/10.1002/imed.1030) summarized the non-BCMA targeted CAR-T cell therapies for MM. Novel targets including CS1, CD38, CD138, NKG2D, CD70, TACI, and etc. might have the potential to prevent the recurrence and enhance treatment efficiency. The review from Elaine Tan Su Yin (https://doi.org/10.1002/imed.1039) summarized the current breakthrough and future perspectives of CD20-targeted CAR-T cell therapy for hematologic malignancies, especially for R/R B-NHL. The review from Yue Huang (https://doi.org/10.1002/imed.1031) summarized the current achievement and potential AML-associated cell markers of CAR-T cell therapy in AML preclinical studies and clinical trials, and discusses the future directions of CAR-T cell therapy in patients with AML. The review from Yuanyuan Hao (https://doi.org/10.1002/imed.1029) summarized the effects of tumor-derived exosomes (TEXs) on the survival and functions of T cell subsets, as well as their clinical applications. This special issue also contains three original research articles reporting clinical trials of CAR-T cell therapy. Linghui Zhou et al. (https://doi.org/10.1002/imed.1036) reported the data of infections post CAR-T cell therapy, and found that it was a common complication in patients with hematological malignancies treated by CD19 CAR-T cells, which means clinicians should pay more attention to such situations. Kaiting Tang et al. (https://doi.org/10.1002/imed.1037) presented three cases of compassionate CAR-T cell therapy in advanced B-ALL, and shared their experiences on treating patients with high disease burden. Yue Huang et al. (https://doi.org/10.1002/imed.1032) reported an R/R ALL patient with high leukemia burden and central nervous system involvement, who responded to donor-derived HLA-matched allogeneic CAR-T treatment and achieved quick CR. We thank all the authors for their insightful contributions. This special issue provides an overview of the current knowledge regarding the most recent advances of CAR-T cell therapy, including CAR-T cell function, diverse applications, and complications with coping strategies. We hope that this issue will appeal to researchers as they explore fundamental and clinical aspects of CAR-T cell therapy.

CAR T-cells effective for post-CART relapse: A new treatment paradigm.

e19508 Background: Chimeric antigen receptor T-cells (CART) induce remarkable responses in B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a challenge. Effective therapies for post-CART relapse are limited but may include infusion of a unique CART construct, a strategy distinct from reinfusion of the same CART product. Given limited data evaluating outcomes of a unique CART as salvage therapy for post-CART relapse, we report on the impact of prior CART constructs on subsequent CART responses. Methods: This was a retrospective review (NCT03827343) of children and young adults receiving CD19 and/or CD22 CART therapy for B-ALL between 7/1/12-12/30/21 at our center. Patients included received at least 2 unique CART constructs at some point in therapy, excluding interim CART reinfusions. CART-A was the first CART construct ever received and CART-B the second unique CART. The primary objective was to evaluate complete remission (CR) rates following CART-A versus CART-B. Results: Of 135 heavily pretreated patients, 54 (40%) received at least one prior CART. The majority (n=37, 68.5%) were male. Median age at CART-A and CART-B was 12.5 (range, 3.3-30.4) and 13.7 years (range, 4.5-30.7), respectively. In 42 (77.8%) patients, CART-B targeted a different antigen than CART-A, primarily due to loss of antigen target after CART-A. CR rate was substantially lower with CART-B (n=35, 64.8%) than with CART-A (n=48, 88.9%, p=0.006) (Table). Still, two (3.7%) patients with CART-A nonresponse attained CR with CART-B. Most CART-B responders (n=31, 88.6%) had CART-B targeting a different antigen than CART-A, suggesting limitations of same antigen targeting even with a unique CART construct. CART-B responses amongst 10 patients with interim hematopoietic stem cell transplantation (HSCT) after CART-A were similar to CART-B responses in those without interim HSCT (5 of 10, 50% vs. 30 of 44, 68.2%, p=0.3). In those where CRS grade was known for both CART infusions (n=40), CRS severity was milder with CART-B (≥grade 3, n=1, 2.5%) than with CART-A (≥grade 3, n=15, 37.5%, p=0.0001). Conclusions: Using an alternative CART for post-CART relapse is effective in a substantial proportion of patients, particularly when targeting a unique antigen. As post-CART relapse occurs more frequently and patients receive multiple CARTs, identifying optimization strategies for CART-B will be critical. Further investigation of indication for CART-B, role of interim HSCT, and optimal timing for sequential CART infusions is underway.[Table: see text]