Alfonso Molina, MD, MPH, discusses a phase 1 trial evaluating Orca-T with allogeneic CAR T-cell therapy in high-risk B-cell acute lymphoblastic leukemia.
Orca-T plus allogeneic CAR T-cell therapy has shown promise in meeting crucial needs for patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), including generating durable remissions with a manageable safety profile, according to Alfonso Molina, MD, MPH.1
Data from a phase 1 trial (NCT05507827), which were presented at the
Orca-T Plus Allogeneic CAR T-Cell Therapy Is Considered Safe and Provides and Durable Remissions in High-Risk B-ALL
Additionally, grade 1 cytokine release syndrome (CRS) was seen in 13 patients, whereas grade 2 CRS was experienced in 3 patients. At a median follow-up of 473 days (range, 214-1180), all patients were in remission and alive, and CAR T cells persisted past 10 days in select patients.
“This trial is revolutionary; the combination of the 2 therapies is a rational approach to treating high-risk B-cell malignancies,” Molina, a clinical fellow at Stanford Health Care in Palo Alto, California, said in an interview with OncLive®.
In the interview, Molina dove into the data from the trial, in addition to where he thinks the combination is headed in the management of B-cell malignancies.
Molina is a hematology and medical oncology fellow at the Stanford University School of Medicine in Palo Alto, California.
Molina: CAR T-cell therapy has revolutionized the B-ALL treatment paradigm. We are currently using CAR T-cell therapy for clearance of minimal residual disease [MRD]; we have learned that it is useful for this. [Regarding] B-ALL, CAR T-cell therapies are available as standard-of-care treatment. The advantages [of CAR T-cell therapy] are that it is good at clearing MRD; we are essentially using the therapy as a bridge to allogeneic transplant.
One of the limitations [of CAR T-cell therapy] is durable remission, for example, with obecabtagene autoleucel [obe-cel; Aucatzyl]. Although [obe-cel] is good at the clearance of MRD, the duration of remission is approximately 11 to 12 months. Due to this, patients often need to receive an allogeneic transplant as a consolidation effort. [These limitations] are some of the reasons why in the phase 1 FELIX trial [NCT04404660], for example, 44.1% of patients had received allogeneic transplant before CAR T-cell therapy, and 18% of patients received allogeneic transplant after CAR T-cell therapy.2 In total, 62.1% of patients [in that trial] received the combination of [obe-cel and transplant], which led to the idea of using a healthy donor for CAR T-cell therapy in efforts to augment durable remission rates.
Orca-T has also been revolutionary in the field. Orca-T donors undergo a large volume apheresis, and cells are separated into 3 compartments. The first [compartment consists of] hematopoietic stem cells, regulatory T cells, and conventional T cells. On the day of the transplant, patients receive hematopoietic stem cells and regulatory T cells. The [rationale behind this] is that regulatory T cells provide an immune barrier that protects against GVHD. Conventional T-cells are then administered on the second day of the transplant to provide the graft-vs-leukemia effect. Due to this process, Orca-T has shown low aGVHD and cGVHD rates, which in turn prompted us to question whether the addition of an allogeneic T cell to the Orca-T platform could augment graft-vs-leukemia effects as long as prolonged durable remissions.
Key eligibility criteria for the trial included adult patients with a high-risk B-ALL diagnosis, defined by features like MRD positivity and Philadelphia chromosome–like ALL.1 Patients needed to be candidates for myeloablative conditioning. All the patients in the trial received myeloablative conditioning. Patients also needed to have an eligible donor; eligibility criteria for donors were that they were either siblings [of patients] or domestic unrelated donors who were matched in 8 out of 8 alleles.
The trial [demonstrated that Orca-T plus allogeneic CAR T-cell therapy] is a safe combination. The median time to platelet engraftment was 15 days [range, 12-33], the median time to neutrophil engraftment was 13 days [range, 10-20], and no patients experienced primary graft failure. CRS was observed in all patients who received the combination; however, all instances were low grade. Eighty-one percent of CRS in patients from the trial was grade 1. There was 1 patient who experienced immune effector cell–associated neurotoxicity syndrome [ICANS], which was also grade 1. All patients [who experienced CRS or ICANS] were [treated for these AEs], and their symptoms were resolved.
In terms of GVHD, 1 patient experienced aGVHD, but it was mild. Two patients experienced cGVHD, with 1 instance being graded as moderate. All 3 [cases of GVHD] were responsive to steroids, and as of the latest assessment, the cases of GVHD in these patients were resolved.
The primary end point of the trial was safety, and it was measured by the absence of grade 3 or 4 aGVHD or the experience of primary graft failure. None of the patients in the trial have experienced these end points, and all our patients are both alive and in remission. The outcomes from the trial are good.
When looking at MRD, 41% of the patient population was MRD positive at the start of treatment, and approximately 1% of patients had active disease. As of our last follow-up, it has been 1 year since the start of treatment for approximately 12 patients and 3 years for approximately 2 patients. [These 2 patients] are MRD positive, but [MRD is] only detectable by next-generation sequencing using clonoSEQ, and their MRD values are downtrending and in the single digits. All our patients are MRD negative by flow cytometry and by BCR-ABL.
Based on these results, we should start applying this method of combining [Orca-T and allogeneic CAR T-cell therapy] for the treatment of these high-risk B-cell malignancies. Currently, we are investigating what is happening with the immune system when patients are administered the combination. Correlative studies are being performed to assess the differences between Orca-T and CAR T-cell therapies’ contributions to effects on the immune system.
A key finding [from this trial] is that the allogeneic CAR T-cells are persisting for a long time. With allogeneic CAR T-cells, one of the issues is that the cells do not persist. But [in this trial], we are seeing cells persist after day 100 by PCR and flow cytometry methods. The cells are detectable in most patients.
Another question that might arise is: What are the infection rates among patients? There was a 60% infection rate [in this trial] but most [of these infections] were bacteremia, which were treated to resolution with IV antibiotics.
Disclosures: Molina had nothing to disclose.
