Genocury Biotech's In Vivo CD19 CAR-T Therapy Shows Promise in Relapsed/Refractory DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, imposing a substantial economic burden on patients and healthcare systems, especially in the first year following diagnosis.

Cost Estimates and Trends:

• First Year Costs: Several studies highlight the considerable costs during the first year. One study found a mean per-patient, per-month cost of US$11,890 for DLBCL. Another study reported even higher costs, with US$15,555 per patient per month within 1 year of diagnosis. A third study found total costs of $137,156 per patient per year for incident patients, with outpatient costs being the primary driver at $88,202 per patient per year.
• Subsequent Years: Costs generally decrease after the first year due to reduced chemotherapy, inpatient admissions, and other outpatient services. However, costs remain substantial, especially for patients requiring additional lines of therapy or stem cell transplantation. One study found mean healthcare expenditures of $111,314 (124.5 days), $88,472 (80.8 days), and $103,365 (70.9 days) for the first, second, and third lines of therapy, respectively. When adjusted to 30-day periods, these costs increased to $26,825, $32,857, and $43,854, respectively.
• Stem Cell Transplantation: Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant costs, particularly in the first year post-transplant (average healthcare costs of $455,741). Although costs decrease over time, they remain high even in the third year ($72,957).
• Relapsed/Refractory DLBCL: Patients with relapsed or refractory DLBCL face a significant cost burden, with expenses increasing with each subsequent line of therapy. In Japan, the median inpatient stay for second- and third-line cohorts was 118 and 116 days, respectively, with inpatient costs accounting for the majority of expenses.
• CAR T-Cell Therapy: Chimeric antigen receptor (CAR) T-cell therapy, while effective, is associated with high upfront costs and potential for costly neurologic adverse events. One study estimated the budget impact of CAR T-cell therapy in Germany to range from 39.4 million to 165.7 million over a 6-year period.
• Out-of-Pocket Costs: A study estimated annualized net out-of-pocket costs for medical services and prescription drugs for adults aged 65 and older to be highest in the initial ($2200 and $243, respectively) and end-of-life phases ($3823 and $448, respectively) of care, and lowest in the continuing phase ($466 and $127, respectively).

Cost Drivers:

Key cost drivers in DLBCL treatment include:

• Chemotherapy: Especially in the first year.
• Inpatient admissions: Particularly for patients with relapsed/refractory disease or those undergoing HSCT.
• Outpatient services: Including physician visits, radiation therapy, and supportive care.
• Novel therapies: Such as CAR T-cell therapy and targeted agents.
• Adverse events: Including infections, cytopenia, and neurologic complications.

Geographic Variations:

While most cost data are from US studies, some studies from Europe and Japan provide insights into regional variations in costs and resource utilization. Further research is needed to fully understand the economic burden of DLBCL across different healthcare systems.

Unmet Needs:

The high cost of DLBCL treatment, especially for relapsed/refractory disease and novel therapies, highlights the need for:

• Cost-effectiveness studies: To guide treatment decisions and resource allocation.
• Cost reduction strategies: To improve access to effective therapies.
• Research on less expensive but equally effective treatments.
• Improved supportive care: To manage adverse events and reduce associated costs.

CD19 CAR-T therapy is being investigated in several other hematological malignancies beyond Diffuse Large B-cell Lymphoma (DLBCL). These include:

• B-cell acute lymphoblastic leukemia (B-ALL): CAR-T therapy has shown remarkable success in treating R/R B-ALL, leading to FDA approval of tisagenlecleucel and brexucabtagene autoleucel. Studies are ongoing to evaluate CAR-T in earlier lines of therapy and in combination with other treatments. Trials are exploring different CAR constructs, dosing strategies, and bridging therapies to optimize efficacy and minimize toxicity. A study utilizing a novel anti-CD19 CAR molecule (CD19-BBz(86)) demonstrated potent anti-leukemia activity without severe CRS or neurotoxicity. Another study explored sequential CD19 and CD22 CAR-T cell therapy in adult R/R B-ALL, showing durable efficacy and a manageable safety profile.
• Chronic lymphocytic leukemia (CLL): While initial results in CLL were less impressive than in ALL or DLBCL, research continues to explore strategies to improve CAR-T efficacy in this disease. Studies are investigating novel CAR designs, combination therapies, and methods to enhance CAR-T cell persistence.
• Follicular lymphoma (FL): CAR-T therapy has shown promising activity in R/R FL, leading to FDA approval of lisocabtagene maraleucel. Trials are evaluating CAR-T in earlier lines of therapy and in combination with other treatments. A study examined real-world outcomes of CAR-T in FL, confirming its efficacy in this setting.
• Mantle cell lymphoma (MCL): CAR-T therapy has demonstrated efficacy in R/R MCL, leading to FDA approval of brexucabtagene autoleucel. Trials are exploring different CAR constructs and treatment strategies to optimize outcomes in this disease.
• Multiple myeloma: CAR-T therapy targeting BCMA has shown promising results in multiple myeloma, leading to FDA approval of several products. Studies are ongoing to evaluate CAR-T in earlier lines of therapy and in combination with other treatments. A study investigated the impact of PPM1D mutations on CAR-T outcomes in multiple myeloma, suggesting that these mutations may predict worse outcomes.
• Other B-cell lymphomas: CAR-T therapy is also being investigated in other B-cell lymphomas, including primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (tFL). A study evaluated the outcomes of CAR-T in tFL, showing similar efficacy and safety compared to de novo DLBCL.
• Autoimmune diseases: Beyond cancer, CD19 CAR-T therapy is being explored in autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis. A case report described the incidental cure of psoriasis in a patient with DLBCL treated with CAR-T therapy.

Intervention models for these trials vary depending on the specific disease and research question. Common intervention models include:

• Single-arm studies: These studies evaluate the safety and efficacy of a single CAR-T product in a specific patient population.
• Randomized controlled trials: These studies compare CAR-T therapy to standard treatments or other experimental therapies.
• Dose-escalation studies: These studies evaluate the safety and efficacy of different CAR-T doses.
• Combination therapy studies: These studies evaluate CAR-T therapy in combination with other treatments, such as chemotherapy, targeted therapy, or other immunotherapies.
• Sequential therapy studies: These studies evaluate the use of CAR-T therapy followed by other treatments, such as allogeneic stem cell transplantation.

Overall, CD19 CAR-T therapy is a rapidly evolving field with ongoing research exploring its potential in a wide range of diseases. Further studies are needed to optimize treatment strategies, minimize toxicity, and expand the reach of this promising therapy to more patients.