Dr. Nirav Shah and colleagues presented this research at the American Society for Hematology (ASH) Annual Meeting held in December 2021 (ASH 2021).
Background:
CAR-T (Chimeric Antigen Receptor T-cell) therapy is a cellular immune treatment that genetically trains an individual’s immune system (specifically the T-cells, which are a type of white blood cell) to recognize and attack cancerous cells. CAR-T involves taking cells from the patient and altering them to add a chimeric antigen receptor, specifically for different cancer types. For example, for chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), CAR T-cells are made to express a receptor for CD19, a marker found on the surface of all B cells. This allows them to attach to cancer cells that express CD19 on their surface. However, one of the challenges is that targeting CD19 alone can lead to downregulation of this protein by cancer cells, and this can lead to relapse with a disease that doesn’t express the target CD19 on the cell surface. In other words, it becomes CD-19negative and escapes detection by anti-CD-19 CAR-T therapies.
Takeaways:
- To overcome the limitation of single antigen CAR-T therapy, scientists created a bispecific CAR T-cell treatment targeting both CD19 and CD20.
- The research presented at ASH 2021 results from a phase 1 clinical trial with bispecific anti-CD19 and anti-CD20 (LV20.19) CAR T-cells manufactured through a slightly different process than previously reported in the group’s original paper.
- This is a phase 1/2 clinical trial evaluating the safety and efficacy of LV20.19 CAR T-cells for relapsed/refractory B-cell NHL.
- In total, 22 pts received LV20.19 CAR T-cells. In addition, there were 11 patients with diffuse large B-cell lymphoma (DLBCL), 8 with mantle cell lymphoma (MCL), and 3 with follicular lymphoma (FL).
- The median age was 63, and the median line of prior therapy was 4.
- One dose-limiting toxicity was when a patient experienced prolonged grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and grade 4 acute kidney injury.
- There were two deaths from infectious complications (pneumonia, sepsis) unrelated to disease relapse.
- Cytokine release syndrome (CRS) occurred in 19 pts (86%). CRS is a condition that can occur after treatment with immunotherapy like CAR-T. Immunotherapy can cause a large, rapid release of cytokines into the blood from affected immune cells. This can cause many symptoms, including fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing.
- ICANS (a.k.a neurotoxicity) occurred in 6 pts (27%). ICANS is another condition that can occur after treatment with immunotherapy. It encompasses neurologic adverse events that can cause confusion, tremors, or difficulty with communication.
- Among all patients, the overall response rate was 91%, with 55% of patients experiencing a complete response.
- 17 patients had measurable residual disease (MRD) testing 1-2 months after treatment, and 13 out of 17 patients were MRD-negative.
- Among the 8 MCL patients, the overall response rate on day 28 was 100% (complete response = 63%), and 6 of 7 evaluated for MRD were negative on day 28.
- At the last follow-up, no MCL patient had relapsed with a median follow-up time of 5 months.
Conclusions:
These results are encouraging and show that patients with relapsed/refractory B-cell NHL treated with bispecific LV20.19 CAR T-cells have a high overall response rate and low rates of grade ≥3 CRS or ICANS. The results from patients with MCL are especially impressive, and this bodes well for the CLL community since they are closely related diseases with similar biology and targets.
Loss of CD-19 has been documented as a cause for failure of CAR-T therapies in CLL though it may occur less frequently than that seen in other lymphomas.
Here is the link to the ASH 2021 abstract for more details.
Watch Dr. Brian Koffman’s monologue on this ASH abstract below.
Take care of yourself first.
Ann Liu, PhD
