Talicabtagene autoleucel (tali-cel) is the first humanized CD19-directed CAR-T cell therapy approved in India for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and B-cell non-Hodgkin lymphoma (B-NHL). Here, we integrated clinical and manufacturing operations through a centralized coordination unit (CCU) and evaluated tali-cel implementation. Patients with r/r B-ALL (n = 105) and r/r B-NHL (n = 145) who underwent leukapheresis between 15 November 2023 and 31 January 2025 across 56 treatment centers were included. The CCU enabled timely delivery, with manufacturing slot allocation within one week of slot request and a median vein-to-vein time of 29 days (range, 16-102), independent of geographic location. In r/r B-ALL patients, the median follow-up was 14 months, and the median overall survival (OS) not reached, and progression-free survival (PFS) was 18 months (range: 9-NR). The 12-month OS and PFS were 64% (95% CI: 53-72) and 55% (95% CI: 45-65). In r/r B-NHL, the median follow-up was 13 months and the median PFS was 11 months (range:7-16) and OS was not reached. The 12-month OS and PFS were 63% (95% CI: 54-71) and 47% (95% CI: 38-56). No patients underwent consolidative stem cell transplantation. Grade 3/4 cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) occurred in 6%, 4%, and 23% of r/r B-ALL and 6%, 3%, and 18% of r/r B-NHL patients, respectively. These findings demonstrate the successful implementation of tali-cel across multiple centers in a large cohort, which might contribute towards improving CAR-T access globally.

Background : Talicabtagene autoleucel (Tali-cel), a second-generation, humanized CAR-T cell therapy targeting CD19, was approved in India in October 2023 for the treatment of relapsed or refractory (r/r) B-cell malignancies. This report presents real-world data on its clinical effectiveness, safety profile, and healthcare resource requirements in patients with r/r B-cell non-Hodgkin's lymphoma (B-NHL) treated across multiple centers in India. Methodology: We performed a retrospective review of patients aged ≥15 years with r/r B-NHL who received Tali-cel as standard-of-care (SOC). Following lymphodepleting chemotherapy, patients were infused with ≥5×10⁶ CAR-T cells/kg in a single dose. Bridging therapy was administered at the treating physician's discretion. Response was evaluated using PET-CT or CT imaging according to Lugano 2014 criteria at regular intervals typically at day 28, month 3(M3), month 6(M6), month 9(M9), month 12(M12) and annually for 5 years. Adverse events of interest—including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell–associated hemophagocytic syndrome (IEC-HS), cytopenias, and hypogammaglobulinemia—were graded using ASTCT guidelines. Additional outcomes such as ICU admission, hospital stay, and mortality were documented. Kaplan–Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS). Results: From the time of approval until May 2025, 60 treatment centers across India administered Tali-cel for B-NHL. A total of 194 patients underwent leukapheresis, 170 received the CAR-T infusion, and 143 were evaluable for safety and efficacy outcome. The manufacturing success rate was 98% (191/194). Fourteen patients died prior infusion. The median patient age was 56 years (range: 17–83), with males accounting for 64% of the cohort. Most patients had received a median of 2 prior treatment lines (range: 1–7), including polatuzumab (14%), and stem cell transplantation (4%). 23% of the patients had bulky disease (largest lesion ≥ 7cm) at enrollment and 79% received bridging therapy prior to CAR-T cell therapy. Median vein-to-vein time was 30 days (range: 16–124). The overall response rate (ORR) was 75% and 60% and CR rate was 57% and 56%at M1 and M3 respectively. The median duration of follow-up was 5 months (range: 1–19). Six month PFS rates was 56%(95% CI: 48-66), while OS rates were 74%(95% CI: 67-83). Median PFS was 10 months, and median OS was not reached. Most common toxicity was cytopenia with incidence of Grade 3-4 (G3-4) in 71% of the patients. Incidence of CRS was 75% (G3-4: 6%), and ICANS was 11% (G3-4: 3%) of the patients. Hypogammaglobulinemia and IEC-HS were observed in 50% and 17% of patients, respectively. Tocilizumab was administered in 63% patients who developed CRS with median dose of 1 (range 1-3). Vasopressor and Corticosteroids was required only in 6% and 8% respectively. IVIG support was required in 34% patients and anakinra for management of IEC-HS was required 75% respectively. 6% of patients required ICU-level care. The overall median hospital stay was 12 days. Conclusion: This real-world analysis demonstrates that tali-cel is a practical, effective, and well-tolerated treatment option for r/r B-NHL in India. As the first large-scale, multicenter evaluation of this therapy in the Indian healthcare landscape, our findings support its broader implementation across various levels of clinical practice.

Background: In India, access to curative therapies for relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) remains limited due to restricted availability of allogeneic transplants and monoclonal antibodies. Talicabtagene autoleucel (Tali-cel), a CD19-directed humanized CAR-T cell therapy, was recently approved as the first commercial CAR-T therapy in India and is priced at nearly one-tenth the cost of similar U.S. therapies. Early intervention with Tali-cel may reduce treatment-related toxicity and healthcare resource utilization (HCRU), offering an affordable therapeutic option in resource-constrained settings. We present real-world data on the clinical outcomes, safety, and HCRU associated with early vs. late use of Tali-cel. Methods: This retrospective real-world study included 118 patients with r/r B-ALL who received Tali-cel between November 2023 and May 2025 in India. Patients were stratified based on timing of relapse: early treatment (first or second relapse) vs. late treatment (≥ third line failure). Clinical efficacy was assessed by bone marrow morphology and flow cytometry, per NCCN guidelines v2.2024.Disease response was assessed at regular intervals typically at day 28, month 3(M3), month 6(M6), month 9(M9), month 12(M12) and annually for 5 years. Progression-free survival (PFS) was analysed using Kaplan–Meier method. Safety outcomes included adverse events of special interest such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell–associated hemophagocytic syndrome (IEC-HS), hypogammaglobulinemia, and cytopenias —graded per ASTCT criteria. HCRU was accessed by hospital length of stay, ICU admission, clinical management of toxicities. Cost estimates were derived from institutional billing and resource use models of public sector tertiary cancer centre in India. Results: A total of 118 patients with r/r B-ALL received tali-cel, of whom 81 patients were treated in early treatment (defined as first or second relapse) and 37 patients in late treatment (≥ third line). Baseline characteristics were well balanced between groups: median age (24 vs. 26 years), male gender (78% vs. 74%), and disease burden at apheresis (3% vs. 2% blasts). Patients treated in early treatment demonstrated significantly better clinical outcomes. The patients with early treatment had overall response rates (ORR) of 93% and 86% at M1 and M3 post tali-cel infusion; in contrast to the late treatment group with 81% and 56% respectively. Estimated PFS at 6 months favoured early treatment (88% vs. 70%), indicating more chances of durable disease control. Early treatment was associated with fewer severe adverse events. ICANS occured in occurred in 6% of early vs. 16% of late patients; with Grade 3-4 incidence in 3% vs. 8%, respectively. Rates of cytopenias were comparable (69% in both groups), as were Grade 3-4 CRS (7% vs. 8%), IEC-HS (22% vs. 18%) and hypogammaglobulinemia (52% vs. 46%). Early treatment significantly reduced health care resource use. Median hospital stay was 6 days in early vs. 12 days in late group (p<0.01). ICU admissions were markedly lower (3% vs. 22%, p<0.01) and ICU stay shorter (median 2 vs. 9 days, p<0.05). Supportive care requirements were reduced: vasopressor use (5% vs. 8%) and corticosteroids (7% vs. 39%, p<0.01) were both lower with early use. Utilization of tocilizumab (72% vs. 62%), anakinra (26% vs. 24%), and IVIG (49% vs. 54%) was similar between groups, reflecting consistent supportive management. Cost modelling revealed a 60% reduction in median hospitalization costs for early-relapse patients, driven by shorter hospital stay, less ICU need, and fewer high-grade toxicities requiring intensive management. Conclusion: In this real-world cohort, patients with early relapse r/r B-ALL treated with tali-cel achieved more durable responses, with higher remission rates and longer progression-free survival compared to those treated later in the disease course. Importantly, early use was associated with lower toxicity, reduced healthcare resource utilization, and a significant reduction in overall cost of care. These findings suggest that early intervention with Tali-cel represents a potentially cost-effective treatment strategy, especially in resource-limited healthcare settings.

INTRODUCTION:CAR-T cell therapy has changed the treatment paradigm for hematological malignancies, offering a curative potential for patients with relapsed or refractory disease. India, with its significant burden of hematological malignancies, faces unique challenges in implementing this therapy. The development of indigenous CAR-T cells has reduced costs substantially, but barriers remain, including limited manufacturing capacity, relatively high costs, and logistical constraints. AREAS COVERED:This article emphasizes the importance of optimized patient selection and triaging of apheresis slots to maximize the benefits of CAR-T cell therapy. The use of efficient bridging therapies and antibody-based approaches are being explored to improve outcomes, particularly in aggressive lymphomas and leukemias. Opportunities lie in leveraging India's growing biotechnology sector for cost-efficient production and in evaluating novel combination therapies to enhance CAR-T cell efficacy. This article also explores the technical and socioeconomic challenges of CAR-T cell development in India and suggests strategies to enhance accessibility, affordability, and implementation. EXPERT OPINION:Ongoing advancements and research may help tailor CAR-T cell protocols to the local population. Future integration of NK cell therapy, TCR-based approaches, and multi-antigen targeting holds promise for enhancing therapeutic efficacy.

Background: BCMA directed CAR-T cell therapies have shown durable responses and improved outcomes in relapsed/refractory multiple myeloma (RRMM). We designed and developed novel humanized BCMA-directed CAR-T cell therapy (hBCMA) with robust activity and low toxicities in preclinical settings (Khan et al., ASH 2024). Here, we report the manufacturing feasibility and Phase I clinical study to evaluate the safety and activity of hBCMA in RRMM in India (CTRI/2025/01/079364). Methods: Phase I trial with primary aim to assess safety by determining the incidence of adverse events and dose-limiting toxicities (DLTs) was initiated on 24/01/2025 upon obtaining regulatory approvals in India. Patients aged 18 and above with RRMM who have received at least two prior lines of therapy or are double refractory to IMiD and PI combination, with measurable disease were enrolled in the study. Prior exposure to BCMA-targeted therapy, ongoing immunosuppressants, history of allogeneic bone marrow transplantation, significant cardiac or CNS issues, and active infections were the exclusion criteria. Dose escalation study was planned at three dose levels (DL): 0.5-2x106 (DL1), 2-5x106 (DL2), 5-10x106 (DL3) CAR-T cells/kg. Leukapheresis was performed with a target collection of 2 × 10⁹ ALC and transported to a centralized manufacturing facility within 24 hours at 2–8 °C. T cells were enriched and activated using magnetic beads, followed by viral transduction and product harvest upon achieving the target CAR-T cell dose using semi-automated process. Patients were subjected to a lymphodepleting regimen with Cy (300 mg/m2, d-5 to d-3) and Flu (30 mg/m2, d-5 to d-3) prior to the CAR-T cells infusion (d0). The toxicity was graded by ASCT guidelines and CTCAE 5.0 and efficacy was assessed by the IMWG Uniform Response Criteria for Multiple Myeloma. Results: As of 31st July 2025, six patients were consented and underwent leukapheresis (DL1 n=4; DL2 n=2) for hBCMA CAR-T cells manufacturing. The median age of the cohort was 57(43-65) years with median lines of therapy of 5(3-7). Leukapheresis yielded sufficient cells, with a median of 2.5 × 10⁹ CD3⁺ cells collected per run. The required dose was achieved by 6-8 days with median CAR expression of 42% (range 19-52) from all patients (100% manufacturing success rate). The final product showed effective distribution of less differentiated T cells (median Naïve (CD45RA+CCR7+): 22%, range 5-24 and Central memory (CD45RA-CCR7+): 21%, range 14-22) suggestive of superior quality immunophenotype of CAR-T cells. One patient was withdrawn post leukapheresis due to deterioration in performance status prior to infusion. Three patients received infusion of hBCMA CAR-T cells at DL1 and one patient received at DL2. The median vein-to-vein time was 26 days(range 19-36). Bridging therapy was given to 50% (3/6) patients. The patients with DL1 were evaluable for safety and early efficacy. DL2 cohort was under evaluation and updated data will be presented at the meeting. Cytopenia was most common toxicity with incidence of Grade 3-4(G3-4) thrombocytopenia (n=2/3), neutropenia (n= 3/3), and anaemia (n=2/3). Cytokine release syndrome (CRS) was reported in 67% (2/3) patients. None of the patients developed G3/4 CRS and ICANS of any grade. At one month post infusion, responses were sCR (n=2) and PR (n=1). The patients maintained response at last follow up (median follow up: 62 days (28-90)). No dose limiting toxicity or treatment related deaths were reported. In vivo CAR expansion was evaluated by qPCR at Day 7, Day 14 and Day 28 until date cut off. Peak expansion was observed on Day 14 (median: 2.6 X 104 CAR copy number/µg gDNA) and maintained CAR persistence at Day 28 (median: 1.4 X 104 CAR copy number/µg gDNA). Conclusion: Early results from the Phase I study demonstrates that low doses of hBCMA CAR-T cells are safe, active, with rapid in vivo expansion in patients with RRMM. The study also indicates the manufacturing feasibility of CAR-T cells from heavily pretreated RRMM patients.

BACKGROUND:In low-income and middle-income counties (LMICs), the outcome of relapsed or refractory B-cell malignancies is poor due to the absence of effective therapies. We report the results of a phase 1/2 study of a novel humanised anti-CD19 4-1BB chimeric antigen receptor (CAR) T-cell therapy, talicabtagene autoleucel, for patients with relapsed or refractory B-cell malignancies. METHODS:This open-label, multicentre, phase 1/2 study was done at six tertiary cancer centres in India. Phase 1 was a single-centre study done in Tata Memorial Hospital, India, in patients aged 18 years or older with relapsed or refractory B-cell lymphomas. Phase 2 was a single-arm, multicentre, basket trial done in five tertiary cancer centres in patients aged 15 years and older with relapsed or refractory B-cell acute lymphoblastic leukaemia or B-cell lymphoma. Eligible patients had a life expectancy of 12 weeks or more, an ECOG performance status of 0-1 (phase 1) or 0-2 (phase 2), and an adequate organ function. Patients underwent apheresis to obtain at least 1 × 109 lymphocytes to manufacture CAR T cells. Lymphodepletion therapy was done with cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2 for 3 days or bendamustine 90 mg/m2 for 2 days. Patients were then infused intravenously with talicabtagene autoleucel 1 × 107-5 × 109 CAR T cells in a fractionated schedule (10%, 30%, and 60%, on days 0, 1, and 2, respectively) during phase 1 or at least 5 × 106 CAR T cells per kg (up to 2 × 109 CAR T cells) on day 0 during phase 2. The primary endpoints were safety (phase 1) and overall response rate (phase 2). The efficacy analysis was done in the efficacy evaluable cohort (all patients who received the target dose and 3 days of lymphodepletion therapy). The safety analysis was done in the safety population (all patients who received talicabtagene autoleucel). The trials are registered with Clinical Trial Registry-India (CTRI/2021/04/032727 and CTRI/2022/12/048211), and enrolment is closed. FINDINGS:Of 64 patients, 14 were enrolled in phase 1 (from May 11, 2021, to May 13, 2022) and 50 were enrolled in phase 2 (Dec 27, 2022, to Aug 31, 2023). The median age of the overall cohort was 44 years (IQR 27-57), and 49 (77%) of 64 patients were male and 15 (23%) were female. In phase 1, no dose-limiting toxicities occurred at doses of 2 × 106-17 × 106 CAR T cells per kg. A dose of at least 5 × 106 CAR T cells per kg was chosen for phase 2 based on a complete response in three of seven patients at this dose. The most common grade 3 or worse toxicities were haematological events: anaemia (35 [61%] of 57 patients), thrombocytopenia (37 [65%] patients), neutropenia (55 [96%] patients, and febrile neutropenia (27 [47%]) patients). There were two treatment-related deaths, one due to febrile neutropenia, immune-effector cell associated haemophagocytic lymphohistiocytosis, and septic shock, and the second due to pulmonary bleed, multiorgan dysfunction syndrome, and cytokine release syndrome. In 51 efficacy-evaluable patients (36 with B-cell lymphoma and 15 with B-cell acute lymphoblastic leukaemia), the overall response rate was 73% (37 of 51; 95% CI 59-83). INTERPRETATION:Talicabtagene autoleucel had a manageable safety profile and induced durable responses in patients with relapsed or refractory B-cell malignancies. This therapy addresses an important unmet need for patients with relapsed or refractory B-cell malignancies in India. FUNDING:Immunoadoptive Cell Therapy (ImmunoACT) and Indian Council of Medical Research (ICMR).

Context Actalycabtagene autoleucel (Actaly-cel) is an indigenously developed, humanized, CD19-directed CAR-T cell therapy, recently approved in India. Understanding the pattern of infections in patients receiving this therapy will help to improve future prophylaxis and management of infections. Objective To determine the incidence, pattern, and outcomes of infections in patients receiving Actaly-cel. Design Single-center retrospective study. Data were extracted from the electronic medical records of the Tata Memorial Hospital. Setting Tertiary referral cancer center. Participants Patients ≥15 years who underwent infusions of Actaly-cel from June 2021 to December 2023. Main Outcome Measures:1) Median number of infections per patient, 2) timeline of infections after infusion, 3) correlation between infection rates and a) absolute lymphocyte count (ALC) and IgG levels at baseline and b) duration of neutropenia, and 4) mortality rate due to infection Results Fortyeight patients, median age 43 years (IQR:27-57), were included. The most frequent indication was refractory DLBCL (62%; n=30/48). Median ALC and IgG level at baseline were 0.08 cells/mm3 (IQR:0.02-0.55) and 820 mg/dL (IQR:568-983), respectively. The median day of neutropenia onset was 2 (IQR:0-4) and the median duration was 9 days (IQR:5-13). The total number of infections documented was 121, with a median per patient of 2 (IQR:1-3). The most common syndromes were culture-negative febrile neutropenia (27%; n=33/121) and upper respiratory tract infection (19%; n=24/121). Sixty-seven infections (55%) occurred from D0-D28 postinfusion; of these, 58% (n=39/67) were confirmed or suspected bacterial infections. The causative organism was identified in 28% (n=35/121): bacteria in 18, viruses in 15, and fungi in 2. There was no correlation between the number of infections and ALC, IgG level at baseline, or the duration of neutropenia. In 8.3% of patients (n=4/48), infections contributed to death. These included suspected bacterial pneumonia (n=1), GI sepsis (n=1), COVID pneumonia (n=1), and neutropenic sepsis (n=1). The median time to death in these patients was 46 days (IQR:32-101) after infusion. Conclusions Patients receiving Actaly-cel primarily developed infections on days 0-28 after infusion. The majority of these were suspected or confirmed bacterial infections. The number of infections per patient did not correlate with ALC, IgG level at baseline, or the duration of neutropenia.

Background: CAR-T cell therapy is effective and used in the second line treatment of relapsed/refractory B-cell lymphoma. However, costs of delivery remain high due to the manufacturing costs and toxicity management requiring specialized care. CARs with lower toxicity profile can improve access and cost-effectiveness of CAR-T cell therapy. We developed a humanized anti-CD19 CAR-T cell therapy, Talicabtagene autoleucel (formerly known as Actalycabtagene autoleucel) with favorable toxicity profile and demonstrated its efficacy in Phase I&II clinical trials (ASH 2022, ASH 2023) leading to its commercial approval in India. We retrospectively analyzed the cohort of patients who received CAR-T in the second line setting on the trial for the safety, efficacy, and feasibility of treatment. Methods: In this exploratory analysis from the Phase I/II trials (CTRI/2021/04/032727 and CTRI/2022/12/048211), r/r DLBCL patients were divided into two cohorts: patients received Tali-cel as second line therapy (cohort 1) or third or later line (cohort 2). Features such as Metabolic Tumor Volume (MTV), T cell characteristics of apheresis material, infusion success rate, response rates and adverse events were studied as patient related parameters. For product related parameters, manufacturing success rate, in-vivo expansion potential and T cell fitness of CAR-T cell product was studied. The post infusion clinical management was focused on utilization of ICU admission rate, duration of hospitalization and other resource utilization for toxicity management. Results: A total of 45 patients diagnosed with r/r DLBCL underwent apheresis in Phase I&II clinical trial. The cohort 1 (n=11 (24%)) had a median metabolic tumor volume of 49.31 (2.05-306) cm3, and IPI score 1(0-3). Four patients (36%) of cohort 1 had extranodal disease. In cohort 2 (n=34 (76%)), the disease phenotype was more aggressive with median MTV of 181.5 (1.91-2813) cm3, IPI score 2(1-4) and 20 patients (59%) had extranodal disease. There was no manufacturing failure in cohort 1 and only 1/34 (3%) in cohort 2. One patient in each cohort failed to receive an infusion due to disease progression. Total 36 patients (n=10 cohort 1, n=26 cohort 2) were evaluable for efficacy analysis (dose of ≥5 x 106 CAR-T cells/kg, and lymphodepletion of Cy/Flu for 3 days). The CR rate (95% CI) in cohort 1 at months 1, 3 and 6 was 70% (39.6-89.2), 70% (39.6-89.2) and 60% (31.2-83.1) respectively. In contrast, the CR rate for cohort 2 was 46% (28.7-64.5), 38% (22.4-57.3) and 27% (13.7-46.0) at months 1, 3 and 6 respectively. No incidence of ICANS (any grade) and ≥ Grade 3 CRS was reported in any group. In virtue of favorable toxicity profile, none of the patients of cohort 1 required ICU admission for toxicity management. However, the ICU admission was 16% (5/32) in cohort 2 patients. The median duration of hospitalization for both groups was 8 days. The requirement for tocilizumab and corticosteroids (cohort 1: 10% vs cohort 2: 6%) was comparable, whereas the transfusion support (cohort 1: 30% vs cohort 2: 44 %) and IVIG treatment (cohort 1: 40% vs cohort 2: 53%) was lower in the patients in cohort 1. The patients in cohort 1 showed higher peak expansion on Day 14 (median, cohort 1: 2.56x105 vs cohort 2: 0.57x105 copies/μg of DNA) and the levels further persisted until last follow-up. Immunophenotypic profiling revealed that patients receiving second line CAR-T therapy showed better T cell fitness. The CAR-T cell products from cohort 1 had a higher percentage of CD8+ naïve cells in apheresis as well as CAR-T cell product, which associated with robust CAR-T expansion and durable response. Conclusion: In this post-hoc analysis,Tali-cel was found to be more well-tolerated, more efficacious, and easier to deliver in the second line setting for r/r DLBCL. Given limited patients in each cohort, further study based on post-marketing surveillance is planned.

Background: Talicabtagene autoleucel (Tali-cel), (formerly Actalycabtagene autoleucel) is a humanized anti-CD19 CAR-T cell therapy, approved by the CDSCO (Indian regulatory agency) in October 2023 based on its efficacy and safety data (ASH 2022, 2023). Since its approval, several centers across India have delivered this commercialized CAR T-cell therapy. In this study, we report the real-world feasibility, access, efficacy, and safety evidence of Tali-cel following commercial approval for relapsed / refractory (r/r) B-cell malignancies. Methods: Patients with r/r B-cell malignancies (r/r B-cell lymphomas (BCL) and acute lymphoblastic leukemia (ALL)) aged ≥ 15 years received Tali-cel from 15th November 2023 till 30th June 2024 as standard-of-care were studied. Patients received a single infusion of Tali-cel at target dose of ≥ 5x106/kg, after conditioning with Flu-Cy or bendamustine. Post CAR-T maintenance was allowed. Tertiary cancer centers across India with expertise to treat hematological malignancies were enrolled for administration after getting trained on the algorithms and clinical management of Tali-cel. Monthly manufacturing slots scheduling, and allocation was done by the central production coordinating unit comprised of production managers and medical advisors. The slot allocation was based on multiple parameters including request initiation time, patient's fitness, disease status, and availability of funds. The feasibility and access were evaluated by manufacturing success rate (MSR), out of specifications (OOS) rate and vein-to-vein time. Efficacy assessments included objective response rate (ORR). Hematological toxicities and adverse events of special interests including Grade 3-4 CRS, ICANS and IEC-HS (Immune-effector cell associated- Hemophagocytic lymphohistiocytosis) (defined as per ASTCT criteria) were analyzed. Results: Nine centres across India participated in the real-world analysis, with 79 patients enrolled. 68 patients have received infusion, 2 patients had manufacturing failure, 5 died before infusion and 4 awaited infusions at cut-off date. Utilization between r/r ALL 56% (44/79) and r/r BCL 44% (35/79) was similar. The median age was 22 (12-64) years for r/r ALL and 53 (17-71) years for r/r BCL patients. The male population was 72% (57/79) and median prior lines of therapy was 3 (1-7) for all patients. The median % blasts in r/r B-ALL at the time of infusion was 2 (0-92), and 31% (11/35) had bulky disease (disease site >7cm) in r/r BCL. Centralized manufacturing model ensured that suitable patients received the manufacturing slots within 30 days. The overall MSR was 97% (77/79) with the OOS rate of 3% (2/77) due to sterility failure, however, the product was successfully delivered upon remanufacturing to both patients. The median vein to vein time was 25 days (16-72). The vein-to-vein time was independent of the proximity of the cancer care centers from the manufacturing site. As of cut-off date, the day 28 response assessment post infusion was done for 48 patients (28 r/r ALL, 20 r/r BCL), with an ORR of 85% (41/48). The remaining 20 patients were yet to be evaluated for response. In r/r ALL cohort, the best ORR was 93% (26/28) with 92% (24/26) MRD negative CR Until the last follow-up, 100% (26/26) of r/r ALL and 80% (12/15) of r/r BCL patients continue to remain in The ORR in the real-world settings were comparable to the pivotal Phase I/II trial (r/r ALL: 73% (11/15) and r/r BCL: 68% (26/38)). Grade 3-4 cytopenia were noted in 64% (18/28) and 80% (16/20) in r/r ALL and r/r BCL cohort respectively. Grade 3-4 CRS developed in 4% (1/28) of r/r ALL and 5% (1/20) of r/r BCL patients. Grade 3-4 ICANS developed in 10% (2/20) of r/r BCL and none in r/r ALL patients. IEC-HS developed in 14% (4/28) of r/r ALL and 15% (3/20) of r/r BCL cohorts. The incidence of hypogammaglobulinemia was 29% (8/28) and 65% (13/20) in r/r ALL and r/r BCL cohorts, respectively. Conclusion: The real-world evidence further confirms the efficacy and safety of Tali-cel in B-cell malignancies. The manufacturing success and safe and effective clinical delivery allow the deployment of CAR-T cell therapy outside the clinical trial settings in India.

LBA12134 Background: Oropharyngeal mucositis is a common toxicity seen in patients with HNSCC on concurrent chemoradiation (CTRT). Oral cryotherapy is effective in preventing oral mucositis in patients on 5FU-based therapy. The effect of oral cryotherapy on mucositis in patients with HNSCC receiving CTRT is not known. Hence, we conducted this study to assess the efficacy of oral cryotherapy. Methods: This was an open-label, randomized study that included adults with HNSCC on adjuvant/radical CTRT, an ECOG PS 0-2, without baseline mucositis or contraindications to oral intake. The patients were randomized 1:1 to the oral cryotherapy (CRYO) arm or control (CONT) arm. All patients in the CRYO arm received oral cryotherapy in the form of ice chips within the first 5 fractions of radiotherapy (RT), and till the end of CTRT or till the development of grade 3 or higher mucositis. Patients were asked to keep ice chips in the mouth, 30 minutes before the start of RT. Once the ice melted, they were asked to swirl the melted ice water in their mouth and gargle with it before swallowing/spitting it. This procedure was repeated for 20-30 minutes until the start of RT and for 10 minutes after RT for the day. The same procedure was followed during chemotherapy (CT) infusion, on other days this procedure was repeated 5-7 times/day. Patients in the CONT arm received CTRT and toxicities were managed as per the institutional standards. Patients were evaluated for mucositis and other toxicities of CTRT (CTCAEv5.0) at baseline and weekly intervals during CTRT and at the first follow-up visit 10-12 weeks after completion of CTRT. The primary endpoint was the incidence of grade 3-5 mucositis at any time during CTRT and up to 3 months after completion. Secondary endpoints were QoL and compliance. Descriptive statistics were performed. The incidence of grade 3 or higher mucositis and other toxicities were compared between the arms using the Chi-Square test. Results: 128 patients were enrolled in the study, 64 in each arm. The median age was 59 years (IQR 40-58.75). Most of the patients were males, 93.75% and 85.9% in the CRYO and CONT arms respectively. Most of the patients had ECOG PS 1, 65.6% and 68.75 % in the CRYO and CONT arm respectively. Most patients (40/64, 62.5%) in both arms received concurrent cisplatin as the radiosensitizer. More patients in the CONT arm (23/64 patients, 35.9%) developed grade 3 or higher mucositis as compared to the CRYO arm (17/64 patients, 26,6%), but this was not statistically significant (p=.340). There was no statistically significant difference in the incidence of grade 3 or higher dysphagia, anemia, neutropenia, rise in creatinine, hyponatremia, or radiation dermatitis between the 2 arms. There were no new safety signals noted with the use of cryotherapy. Conclusions: Although cryotherapy reduced the incidence of grade 3-5 mucositis, it was not significant and its efficacy was not established. Clinical trial information: CTRI/2020/07/026657 .

Background: A high incidence of severe toxicities especially grade 3/4 immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS), need for hospitalization, and the cost of supportive care is an hindrance to the implementation of CAR-T cell therapy for low and middle income countries (LMICs). To address these limitations, we designed a novel humanized CD19 CAR and demonstrated a favorable balance of efficacy to toxicity in the preclinical model and in the first-in-human Phase I study (Dwivedi et al. Mol Cancer Ther. 2021, Karulkar et al. ASH 2022). Here, we quantified the healthcare resource utilization (HCRU) and associated cost of clinical management of Actalycabtagene autoleucel (Actaly-cel) in India from an ongoing Phase I/II study in B-cell malignancies. Methods: This is a retrospective analysis of the HCRU costs of patients with r/r B-cell malignancies treated on Phase I/II study with Actaly-cel at 3 centers in India between June 2021 through July 2023. The key components of HCRUs are defined in Table 1 and were quantified from the electronic records from the time of enrolment till their last follow-up. Once enrolled, bridging therapy was allowed at investigator's discretion. After lymphodepletion (LD) with a fludarabine plus cyclophosphamide (FC) regimen for 3 days, patients received Actaly-cel at a target dose ≥ 5 million CAR-T cells/kg (upper limit; total 2 x10 9). The patients were monitored for toxicities particularly CRS, ICANS and cytopenias, as inpatient (non-HEPA filtered rooms) for at least a week. CRS and ICANS were graded as per ASTCT grading system and cytopenias as per CTCAE v5. Results: Total 59 patients were enrolled in this study and 47 patients received the infusion. Thirty seven patients (r/r lymphoma; n=28, r/r B-ALL; n=9) who completed 28 days post-infusion were evaluable for HCRU analysis. The median age was 37 years (16-71). The median follow-up of the cohort was 60 days (21-644); 19% (7/36) and 11% (4/36) patients completed 6 months and 12 months follow-up respectively. Among all patients (n=37) who received LD therapy, 46% of lymphoma patients received LD in the outpatient setting while 78% of B-ALL patients required hospitalization for LD. The median hospitalization period post Actaly-cel infusion was only 8 days (range: 7-17 days) in the lymphoma cohort, and 13 days (range: 7-19 days) for B-ALL patients. Importantly, none of the lymphoma patients required ICU admission, and only one B-ALL patient required ICU admission for management of adverse events. In the lymphoma cohort, 54% (15/28) of patients developed Grade 1/2 CRS and none had grade >/=3. A single dose of tocilizumab was given to 36% (10/28) of patients and only 4% (1/28) received tocilizumab plus corticosteroids. None of the patients required vasopressor support. Majority of B-ALL patients developed CRS. The incidence and severity of CRS was as follows: G1; 44% , G2; 11% and G3; 22%. There were no grade 4/5 CRS events. While 11% (1/9) of patients received a single dose of tocilizumab, 44% (4/9) received tocilizumab in combination with corticosteroids. Vasopressors were required in 22% of patients. None of the patients developed ICANS of any grade . Most patients (lymphoma and B-ALL) developed hematological toxicities(Table 1). The severity of Grade 3-4 was more prevalent in the B-ALL cohort. IVIG was administered to 25% of lymphoma and 22% of B-ALL patients. The induction and severity of the above toxicities were not dependent on the Actaly-cel dosage (median: 9 x 10 6 ;range: 2 x 10 6-21 x 10 6 CAR-T cells/kg). The projected production cost of Actaly-cel in the regional decentralized manufacturing model at the scale of 300 patients/year is ~15,000 USD per patient. The mean cost of HCRU for clinical management (until last follow-up) per patient was ~ 4,400 USD in an academic centre (lymphoma; ~4,000 USD, B-ALL; ~5,565 USD) and interestingly, only about 14% of these costs were incurred due to inpatient management (Figure 1). Conclusions: Actaly-cel was efficacious, with no incidence of ICANS and manageable CRS across a wide dose range. More importantly, this study reported low HCRUs due to negligible ICU admission and shorter duration of hospitalization, ensuring potential usage of Actaly-cel in outpatient settings, and ultimately improving the access and feasibility of CD19 CAR-T cell therapy in resource constrained settings such as LMICs.

Pantoprazole decreases the acidity of the tumor microenvironment by inhibiting proton pumps on the cancer cell. This possibly leads to increased sensitivity to cytotoxic therapy. We conducted a phase I/II randomized controlled trial in adult patients with head and neck squamous cell carcinoma (HNSCC) planned for first-line palliative chemotherapy. Patients were randomized to chemotherapy + / − intravenous (IV) pantoprazole. The primary endpoint in phase I was to determine the maximum safe dose of intravenous pantoprazole, whereas it was progression-free survival (PFS) in phase II. The dose of IV pantoprazole established in phase I was 240 mg. Between Nov’18 and Oct’20, we recruited 120 patients in phase II, 59 on pantoprazole and 61 on the standard arm. Median age was 51 years (IQR 43–60), 80% were men. Systemic therapy was IV cisplatin in 22% and oral-metronomic-chemotherapy (OMC) in 78%. Addition of pantoprazole did not prolong PFS, which was 2.2 months (95% CI 2.07–3.19) in the pantoprazole arm and 2.5 months (95% CI 2.04–3.81, HR, 1.14; 95% CI 0.78–1.66; P = 0.48) in the standard arm. Response rates were similar; pantoprazole arm 8.5%, standard arm 6.6%; P = 0.175. Overall survival was also similar; 5.6 months (95% CI 4.47–8.51) in the pantoprazole arm and 5.4 months (95% CI 3.48–8.54, HR 1.06; 95% CI 0.72–1.57; P = 0.75) in the standard arm. Grade ≥ 3 toxicities were similar. Thus, pantoprazole 240 mg IV added to systemic therapy does not improve outcomes in patients with advanced HNSCC.

The advancements in treatment strategies for cancer in Adolescent and Young Adults (AYAs) and early diagnosis has led to an increase in the cure rate and an increase in the number of AYA cancer survivors. The AYA patient is defined as an individual 15 to 39 years of age at the time of initial cancer diagnosis. AYA cancer survivors are at increased risk of developing various physical and psychosocial issues which vary from those in older adults. There are very few integrated survivorship programmes for AYA cancer survivors in India and this is a huge unmet need. This online survey was directed at oncologists from various major specialties in India, with an interest in the care of AYA cancer patients and survivors. Oncologists practicing in India were sent the survey questionnaire through Google link via e-mail. Data was collected in SPSS and descriptive statistics were performed. We received 100 responses from June 2021 to September 2021 from oncologists all over India. 85% of respondents were medical oncologists, with 59% working at academic centers. Among oncologists who responded to this survey, 74% reported that AYA cancer survivors comprised ≤ 25% of their clinical practice. Major issues faced by most of the survivors included fatigue, anxiety, depression, fear of recurrence, and financial and social issues. Although 88% of the respondents reported the need for a separate follow-up clinic for AYA survivors, only 32% had a dedicated cancer survivor clinic or program at their center. Half of these oncologists had a team of multidisciplinary care providers in their clinic. 58% of the respondents reported that more than 50% of the survivors have resumed their normal life. There is an unmet need for specialized care for AYA cancer survivors in India. Only 32% of oncologists have dedicated clinics for AYA cancer survivors. There is a need to develop survivorship programs for AYA survivors across the country.

Background: Commercially approved CD19 CAR-T cell therapies are effective in r/r B cell malignancies, but are associated with significant albeit manageable toxicities. These toxicities contribute to significant morbidity. We have developed a novel, humanized CD19 CAR-T cell therapy, Actalycabtagene autoleucel (Actaly-cel) and previously reported the safety in Phase I study (Dwivedi et al. Mol Cancer Ther.2021, Karulkar et al. ASH 2022). Here, we present the pooled results from Phase I and a planned interim analysis of the Phase II study evaluating Actaly-cel. Materials and methods: The Phase I study (n=10) was a single-center trial to test the safety of Actaly-cel at a dose of 1x10 7 to 5x10 9 CAR-T cells in patients with r/r DLBCL, tFL and PMBCL (CTRI/2021/04/032727). The Phase II study (n=50) was a single-arm, multi-center study conducted across 3 centers in India (CTRI/2022/12/048211). Patients with r/r B-cell malignancies (including aggressive and indolent B-cell lymphomas and acute lymphoblastic leukemia) aged ≥ 15 years, with normal organ function, ECOG PS 0-2 and measurable disease were eligible. Actaly-cel was manufactured using an integrated semi-automated system. Bridging therapy was allowed at the clinician's discretion. Patients received infusion of Actaly-cel two days after conditioning with fludarabine plus cyclophosphamide. The target dose was ≥5x10 6/kg CAR T-cells (efficacy-evaluable cohort), however doses of ≥0.5x 10 6/kg CAR-T cells were allowed. Patients who received Actaly-cel at any dose were considered in the safety analysis. The primary endpoint was objective response rate, with duration of response, adverse events, PFS and OS as the secondary endpoints. A Simon II-stage design was used to test the hypothesis that the ORR would increase from 25% (historical data) to 40% (⍺- 0.1 and β- 0.2), >15 responses were required out of 50 patients to reject the null hypothesis. The CRS and neurotoxicities (ICANS) were graded and treated as per ASTCT guidelines, other toxicities were graded as per CTCAE v5. Exploratory studies were performed to study the correlation between patient and product related characteristics with response. Results: A total of 59 patients with r/r DLBCL (41), ALL (16) and indolent lymphomas (2) were enrolled (Phase I; 06/2021 till 06/2022 and Phase II; 12/2022 till 07/2023), 56 underwent leukapheresis (ITT set) and 47 received Actaly-cel (safety set). 43 patients received the target dose (Figure 1A). The median age was 43 years (16-71) with 46 (65%) male patients. Patients had a median of 2 prior lines of therapy (1-6), 65% had refractory disease,25% of lymphoma patients had bulky disease, and the median bone marrow blast was 69% (6-98%) in the B-ALL cohort. The median vein-to-vein time was 17(7-132) days. Total 78%(33/43) patients reached the day 28 timepoint at the time of analysis (Figure 1B). The ORR was 70% (23/33), including 58% (19/33) with a CR. In the lymphoma cohort, the ORR was 71%(17/24) and CR was observed in 54%(13/24), while in the leukemia cohort, the CR rate was 66% (6/9, n=5 MRD negative). The median follow-up of evaluable patients was 57 days (21-453). All nine patients and 3 out of 4 patients maintained the response after 3 months and 12 months follow-up, respectively. None of the patients developed ICANS of any grade. CRS developed in 22/33(66%) cases (grade 1/2 in 61%, grade 3/4 in 6%). Of note, no grade >3 CRS was noticed in the lymphoma cohort. Grade 3/4 cytopenias developed in all cases. The median duration of neutropenia was 7 (4-32) days. On Day 28, grade 3/4 neutropenia was observed in 11/33(33%) cases, grade 3/4 thrombocytopenia was observed in 7/33 (21%). Only 1(3%) patient required ICU admission, 2(6%) required vasopressor support, tocilizumab was administered to 18 (55%) patients, median 1 dose (1-4) and steroids were used in 5 (15%) cases. Patients were hospitalized for a median of 8 days (7-19 ). There were no treatment-related deaths. On exploratory analysis, higher CAR-T dose, fewer prior lines of therapy and higher peak CAR-T copies/µg DNA correlated with response. Conclusions: Actaly-cel demonstrated efficacy in r/r B-cell malignancies with a very favorable safety profile. The absence of ICANS, shorter duration of cytopenias and a lower incidence of grade 3/4 CRS makes it one of the safest CD19 CAR-T cell therapy products. Actaly-cel can improve the ease of delivery of CAR T-cell therapy in a wide-range of settings.

Background: Malignant testicular neoplasms constitute about 1% of all cancers in males. This is one of the most common tumours in adolescents and young adult males. After the introduction of cisplatin-based chemotherapy, the survival of germ cell tumour patients, even those with poor prognostic risk factors, has significantly improved over the years. Second-line chemotherapy in patients who have progressed over the first-line cisplatin-based chemotherapy has shown convincing 5 years of overall survival (OS). Methodology: This study is a retrospective analysis of testicular cancer patients from 2014 to 2020 who have received salvage chemotherapy treatment at Tata Memorial Centre. Patient demographics, tumour characteristics and treatment details were recorded in a specific format, and progression-free survival and OS were analysed along with response to therapy. Results: A total of 46 testicular cancer patients from 2014 to 2020, who received second-line chemotherapy, were analysed from the database maintained at our hospital. The median age at diagnosis was 29.5 (18-60) years. Most of the patients (30, 65.2%) presented with lung metastasis and 11 (23.9%) patients with liver metastasis. Most of the patients (21, 45.6%) received vinblastine, ifosfamide and cisplatin, whereas 13 (28.2%) patients received paclitaxel, ifosfamide and cisplatin regimen and 7 (15.2%) patients received GemOx regimen as the second-line chemotherapy. Median OS was observed to be 33.97 months and median progression-free survival was 29.01 months. Conclusion: Second-line chemotherapy in testicular germ cell tumours can result in long-term disease control and all patients who are fit to tolerate second-line therapy should be offered it. Patients with relapsed seminoma did better than relapsed non-seminomatous germ cell tumours.

Background:Surge of SARS CoV-2 infections ascribed to omicron variant began in December 2021 in New Delhi. We determined the infection and reinfection density in a cohort of health care workers (HCWs) along with vaccine effectiveness (VE) against symptomatic infection within omicron transmission period (considered from December 01, 2021 to February 25, 2022. Methods:This is an observational study from the All India Institute of Medical Sciences, New Delhi. Data were collected telephonically. Person-time at risk was counted from November 30, 2021 till date of infection/ reinfection, or date of interview. Comparison of clinical features and severity was done with previous pandemic periods. VE was estimated using test-negative case-control design [matched pairs (for age and sex)]. Vaccination status was compared and adjusted odds ratios (OR) were computed by conditional logistic regression. VE was estimated as (1-adjusted OR)X100-. Findings:11474 HCWs participated in this study. The mean age was 36⋅2 (±10⋅7) years. Complete vaccination with two doses were reported by 9522 (83%) HCWs [8394 (88%) Covaxin and 1072 Covishield (11%)]. The incidence density of all infections and reinfection during the omicron transmission period was 34⋅8 [95% Confidence Interval (CI): 33⋅5-36⋅2] and 45⋅6 [95% CI: 42⋅9-48⋅5] per 10000 person days respectively. The infection was milder as compared to previous periods. VE was 52⋅5% (95% CI: 3⋅9-76⋅5, p = 0⋅036) for those who were tested within 14-60 days of receiving second dose and beyond this period (61-180 days), modest effect was observed. Interpretation:Almost one-fifth of HCWs were infected with SARS CoV-2 during omicron transmission period, with predominant mild spectrum of COVID-19 disease. Waning effects of vaccine protection were noted with increase in time intervals since vaccination. Funding:None.

LBA6016 Background: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC) are accessible to only 1-3% of patients in low and middle-income countries due to cost. In our previous study, metronomic chemotherapy (MC) improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low dose nivolumab to MC improved the overall survival. Methods: This was a randomised phase 3 superiority open-label study. Adult patients with relapsed -recurrent or newly diagnosed advanced HNSCC being treated with palliative intent with ECOG PS 0-1 were eligible. Patients were randomised 1:1 to MC consisting of methotrexate 15 mg/m2 PO weekly, celecoxib 200 mg PO daily and erlotinib 150 mg PO daily, or MC with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Therapy was continued until disease progression or intolerable adverse events. Response assessment (RECIST version 1.1) was performed every 2 months. The primary endpoint was 1-year overall survival (OS) and this was a pre-specified interim analysis with the nominal p-value for efficacy being 0.006. Results: 151 patients were randomised, 75 in MC and 76 in the MC-I arm respectively. The addition of low dose nivolumab led to an improvement in the 1-year overall survival from 16.3% (95%CI 7.95-27.4) to 43.4% (95% CI 30.8-52.3) [Hazard ratio-0.545; 95%CI 0.362-0.82; P=0.00358]. The median overall survival in MC and MC-I arms was 6.7 months (95%CI 5.83 -8.07) and 10.1 months (95%CI 7.37-12.63) respectively (P=0.0052). The median progression-free survival in MC and MC-I arms was 4.57 months (95%CI 4.2 -5.3) and 6.57 months (95%CI 4.43-8.9) respectively (P=0.0021). Response rate in MC and MC-I arm were 49.3% (95% CI 37.8-60.8) and 65.2% (95%CI 53.4-75.4) respectively (P=0.085). The rate of grade 3 and above adverse events was 50% and 46.1% in MC and MC-I arm respectively (P=0.744). Conclusions: In this first-ever randomised study, the addition of low dose nivolumab led to improved overall survival and is an alternative standard of care for those who cannot access full dose nivolumab. Clinical trial information: CTRI/2020/11/028953.

BACKGROUND:To fill the gap in patient-reported outcome (PRO) assessment in children with cancer in India, we planned to adapt domains from the HealthMeasures Patient Reported Outcomes Measurement Information System (PROMIS) tool. This study attempted to identify and pool outcomes relevant to children with cancer and their caregivers in Northern India.METHODS:The study was qualitative and conducted through focussed group discussions (FGDs) and in-depth interviews of children with cancer and their caregivers. Content analysis of transcripts from the sessions was done. The collected themes were collated with existing item banks of the PROMIS tool and new concepts unique to our population were compiled.RESULTS:A set of three FGDs and 14 interviews each for children and their caregivers were conducted. Following content analysis, 121 themes were identified including 10 new concepts. Themes pertaining to the physical domain were cited most. The theme distribution across the three domains was similar among children and caregivers. In the survivor cohort, the relative frequency of mention of psychological and social themes was higher compared to the whole cohort. Themes pertaining to mobility, cognitive dysfunction and peer relationships were more common among survivors.CONCLUSIONS:This qualitative study in children with cancer and their caregivers in India has facilitated a better understanding of the issues pertaining to cancer care that are of most importance to its stake holders. The themes collected may be used to formulate a PRO tool uniquely tailored for use in this population.