Emerging CAR T-Cell Therapies in Large B-Cell Lymphoma
In an interview with Targeted Oncology, Frederick Locke, MD, discussed the mechanism of action of 2 allogeneic CD19-directed CAR T-cell products and next steps for their evaluation for the treatment of patients with LBCL.
Frederick Locke, MD
Two allogeneic CD19-directed chimeric antigen receptor (CAR) T-cell therapies are currently under investigation for patients with large B-cell lymphoma (LBCL): ALLO-501 and ALLO-501A.
ALLO-501 is being studied in the single-arm, open-label, phase 1/2 ALPHA2 study (NCT04416984). The trial plans to enroll 100 patients with histologically confirmed LBCL who have at least 1 measurable lesion, relapsed/refractory disease after at least 2 lines of chemotherapy, an ECOG performance status of 0-1, and adequate hematological, renal, and liver function.1
Patients enrolled are being treated with ALLO-501A in addition to ALLO-647 and lymphodepletion chemotherapy consisting of fludarabine and cyclophosphamide. The primary end points of the study are to assess dose-limiting toxicities and objective response rates (ORR).
An identical drug, ALLO-501A, is also being evaluated. According to Frederick Locke, the main difference between the 2 agents is that ALLO-501A has no rituximab (Rituxan) kill switch. Both ALLO-501 and ALLO-501A include a gene editing component that allows them to be used in combination with chemotherapy and a CD52-directed CAR T product.
According to long-term follow-up data from the phase 1 ALPHA/ALPHA2 trials, ALLO-501 and ALLO-501 A each led to durable complete responses (CR) among patients with LBCL.2 Among 12 patients treated with the phase 2 regimen, the ORR was 67% with a 58% CR rate, At 6 months, 5 patients (42%) maintained a CR, and 4 of the 5 CRs (80%) remained ongoing after 6 months.
“We're pleased with the durability of results from these phase 1 studies. In fact, we see multiple patients who are in remission over 2 years out from an infusion of these CAR T cells. That has allowed us to move forward with the phase 2 portion of the trials, testing them out on a larger scale across more institutions worldwide, to see if we can induce durable remissions and potentially get FDA approval,” Locke, a medical oncologist and translational researcher in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center told Targeted OncologyTM, in an interview.
Chimeric antigen receptor T-cell therapy © Maverick- stock.adobe.com
In the interview, Locke further discussed the mechanism of action of 2 allogeneic CD19-directed CAR T-cell products and next steps for their evaluation for the treatment of patients with LBCL.
Targeted Oncology: Can you discuss ALLO-501 and ALLO-501A, and how they work?
Locke: ALLO-501 and ALLO-501A are off-the-shelf allogeneic CD19-directed CAR T-cell therapies. The only difference between ALLO-501 and ALLO-501A is that ALLO-501A has removed a rituximab kill switch, which was present in ALLO-501. Otherwise, they're identical. These CAR T cells have gene editing. Not only do they express the CD19 CAR, but they’re gene edited. The track locus is removed so that the T cell receptor is not expressed and therefore, the cells are unlikely to cause graft-versus-host disease.
The CAR T cells are gene-edited so that CD52, which is a cell surface protein that's on immune cells, is removed from the CAR T cells and that allows us to also give an antibody against CD52 as part of the conditioning chemotherapy regimen, which is ALLO-647. It's a monoclonal antibody against CD52, which has been removed from those CAR T cells.
Can you discuss some of the currently available CAR T cell products for large B-cell lymphoma?
The current landscape of CAR T-cell therapy for DLBCL includes 3 FDA approved treatments; axicabtagene ciloleucel, tisagenlecleucel [Kymriah], and lisocabtagene maraleucel [Breyanzi]. Now, 2 of those are approved as second line therapy based upon recently reported randomized phase 3 trials, that's axicabtagene ciloleucel, or axi-cel, and lisocabtagene, or liso-cel. Those 2 are approved as second line therapy [and] all 3 are approved as third or later line therapy for [patients with] large B-cell lymphoma.
These are autologous CAR T cells, meaning we take the patient's own T-cells out of their blood through a procedure called leukapheresis. They have to sit on a machine for half a day, the cells get shipped to a manufacturing facility where they're turned into CAR T cells, [and] that process takes at a minimum 3 weeks, and in fact, oftentimes can take 4 to 6 weeks to get those cells back. Patients have to wait, and some patients progress while they're waiting. An off-the-shelf product like ALLO-501 or ALLO-501A would be beneficial because we could just give it to the patient without having to wait for making these autologous CAR T-cell products.
Can you discuss the background, methods, and design of those 2 studies?
These are phase 1 clinical trials designed to test out the safety and effectiveness of these therapies. They include testing out the number of cells to be given of ALLO-501 and ALLO-501 A. It also includes testing out the lymphodepletion regimen of fludarabine and cyclophosphamide, which is commonly used for all CAR T-cell therapies, and the addition of ALLO-647, that monoclonal antibody against CD52. These trials tested out different regimens and schedules of the therapies, and we showed that it can effectively and safely induce remissions and in fact, long-term remissions in patients with diffuse large B-cell lymphoma.
A phase 2 trial was granted regenerative medicine advanced therapy designation. Can you discuss what this might mean for these products moving forward?
We're pleased with the durability of results from these phase 1 studies. In fact, we see multiple patients who are in remission over 2 years out from an infusion of these CAR T cells. That has allowed us to move forward with the phase 2 portion of the trials, testing them out on a larger scale across more institutions worldwide, to see if we can induce durable remissions and potentially get FDA approval. The designation by the FDA simply highlights how this is an exciting and promising new therapy, and it gives it some priority for us for the review and to get an approval if the phase 2 trial demonstrates safety and effectiveness in a larger number of patients that we've treated today.
What are the next steps for this study?
In the phase 1 portions of the ALLO-501 and ALLO-501 A studies, we treated a number of patients with relapsed refractory large B-cell lymphoma. In fact, 33 in total who got the CAR T cells manufactured in the final version that we're using in the phase 2 study. A number of those patients had complete responses, and durable complete responses, which is very promising. We saw that this could be safely given to our patients.
Overall, 58% of patients who had relapsed/refractory large B-cell lymphoma out of those 33 had a response. If you look at the patients who would be eligible for our phase 2 study, which was 12 patients, the uniform manufacturing process, and a single infusion of CAR T cells, 67% responded, and 58% had a complete response. Forty-two percent of those patients, or five out of the 12, had ongoing remission at 6 months after infusion, which is a long time point in large B-cell lymphoma, and some are ongoing beyond 24 months. We're encouraged and therefore are enrolling on the phase 2 study now. We are hopeful that we could get this therapy approved and have it be available to patients so they could very quickly get allogeneic off-the-shelf CAR T cells for their patients.
What is the importance of continuing to study different CAR T-cell therapies and to continue advancing this space?
We know that CAR T cells can be effective for multiple B-cell malignancies, and for multiple myeloma, or plasma cell disorders. Certainly, we are hopeful we can get these therapies out for patients with solid tumors, but I think the real importance of these studies is that this would potentially be the first allogeneic off-the-shelf CAR T-cell therapy for patients. We think it will increase access and more patients will be able to get CAR T-cell therapy, because we have a safe and effective therapy that could be given very rapidly to patients in need. Ultimately, we think that this can increase access to patients and ultimately improve outcomes.
