Matthew Frank, MD, PhD, assistant professor, medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, discusses findings from prior research investigating a CD22-directed CAR T-cell therapy (CAR22) that informed the rationale for launching a phase 1 trial (NCT04088890) with this agent in patients with relapsed/refractory large B-cell lymphoma (LBCL).

At the 2023 EHA Congress, investigators shared results from a single-institution trial evaluating the use of CAR22 in patients with relapsed/refractory LBCL who have progressed on a prior CD19-directed CAR T-cell therapy. Notably, 41 patients were enrolled in the trial, and 1 patient withdrew from the study, leaving 40 evaluable patients. Of these patients, 38 had successful CAR22 manufacturing. Moreover, the investigators reported that CAR22 elicited an overall response rate of 68% at a median follow-up of 22.8 months, and 53% of patients achieved a complete response.

Although CD19 is an attractive target for CAR T-cell therapy, it can become downregulated, and its expression can be lost, Frank begins. Therefore, seeking alternative antigens is important, as there are many patients who would benefit from enrolling in clinical trials investigating therapies with other targets, Frank explains. Potential targets include CD22, CD20, CD79a, and CD79b, making for a lot of options for investigators to consider when designing future trials, he adds.

CD22 is highly and uniformly expressed in most B-cell malignancies, including lymphoma, Frank expands. Investigators launched this phase 1 trial based on this previous knowledge, as well as previous impressive results derived from the National Cancer Institute, which evaluated the same CD22-directed CAR T-cell therapy in children with leukemia, he emphasizes. Notably, this previous research revealed high response rates with CAR22, Frank says. Therefore, the phase 1 trial investigators were interested in evaluating the efficacy of this agent in adult patients with leukemia and lymphoma, Frank concludes.

Videos

Matthew Frank, MD, PhD, discusses findings from prior research investigating a CD22-directed CAR T-cell therapy that informed the rationale for launching a phase 1 trial with this agent in patients with relapsed/refractory large B-cell lymphoma.


Dr Frank on the Background of Investigating CAR22 Therapy in Relapsed/Refractory LBCL

Matthew J. Frank, MD, PhD, assistant professor, medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, lead investigator, clinical trials, Stanford Health Care, discusses remaining questions regarding treatment sequencing following preliminary results from a phase 1 trial (NCT04088890) of a CD22-directed CAR-T therapy (CAR22) in relapsed/refractory large B-cell lymphoma (LBCL).

At the 2023 EHA Congress, investigators shared data from a single-institution, phase 1 trial showing that a single infusion of CAR22 cells in this patient population (n = 38) elicited a best overall response rate of 68% and a complete response rate of 53%.

More research is needed to answer remaining sequencing questions, Frank begins. However, antigen loss remains a problem within this treatment landscape and inrecent trials, antigen levels were downregulated in patients whose disease relapsed, as well as in patients with low antigen levels or no expression of CD22, he explains. A way to address this unmet need may be to observe antigen levels, and identify whether a patient has CD19, CD20, or CD22 antigens, Frank adds. Notably, another area of interest to help address these questions is in the use of technology. Although current methods for detecting antigen levels, such as IHC, are limited, optimizingthese methods, by using flow-based methods, for instance, will increase the accuracy of measured antigen levels, he emphasizes.

Moreover, with the addition of emerging agents in this arena that target CD19 and CD20, investigators may want to use combinations, including triplets, Frank expands. It remains unknown whether using all agents in a single cell is more beneficial thanusing different cells. This question will have to be answered CAR by CAR, Frank notes. Sequential CARs will continue to be investigated in the future as well, as these have been shown to be feasible and effective, Frank explains.

Mechanisms of resistance, which are universal, will also continue to be investigated, Frank continues. Identifying CD58, which prevents CAR T-cells from being stimulated, will also be an area of interest, in addition to designing better CARs that don’t depend on CD58 signaling to activate, Frank concludes.

Matthew J. Frank, MD, PhD, discusses remaining questions regarding treatment sequencing following preliminary results from a phase 1 trial of a CD22-directed CAR-T therapy in relapsed/refractory large B-cell lymphoma.


Dr Frank on Sequencing Questions With CAR22 in Relapsed/Refractory LBCL

Matthew Frank, MD, PhD, assistant professor, medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, discusses preliminary results from a phase 1 trial (NCT04088890) of a CD22-directed CAR-T therapy (CAR22) in relapsed/refractory large B-cell lymphoma (LBCL).

The single-institution trial evaluated CD22-directed CAR-T therapy in patients with relapsed/refractory LBCL who progressed on prior CD19 CAR T-cell therapy. A total of 41 patients were enrolled, although 1 patient withdrew from the study. Of the remaining 40 patients, 38 had successful CAR22 manufacturing. The overall patient population was heavily pretreated, with median of 4 prior lines of therapy, Frank notes. Moreover, 79% of patients had elevated pre-LD lactate dehydrogenase, and one-third of patients had never previously experienced a complete response, Frank emphasizes.

Initial findings from the full dataset were reported at the 2023 EHA Congress. At a median follow-up of 18.4 months, CAR22 produced an overall response rate (ORR) of 68%, and 53% of patients achieved a complete response (CR) in the total population, Frank reports.

The agent produced less toxicities than most standard CAR T-cell therapies and was deemed safe, Frank continues. In the 29 patients who received CAR22 at dose level 1 of 1 x 10

 CAR+ cells/kg, all instances of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were grade 1/2. However, signals of CAR-hemophagocytic lymohistocytosis (HLH), which is characterized by high ferritin levels, cytopenias, coagulopathy, and liver abnormalities, he explains. Five patients experienced this adverse effect (AE), 2 of which received dose level 2 (3 x 10

 CAR+ cells/kg), Frank adds. However, all 5 patients experienced a CR.

Additionally, differences in survival outcomes between dose levels were numerically, but not statistically different, Frank says. The ORRs were 66% with dose level 1 and 78% with dose level 2. CR rates were also similar at 52% vs 56%, respectively.

The higher rate of CAR-HLH and higher-grade CRS associated with dose level 2, combined with comparable efficacy between dose levels, led to the selection of dose level 1 as the recommended phase 2 dose, Frank concludes.

Disclosures: Dr Frank reports participation on scientific advisory boards for Adaptive Biotechnologies, Kite-Gilead, and Cargo; and industry-contracted research for Allogene Therapeutics, Adaptive Biotechnologies, and Kite-Gilead.

Matthew Frank, MD, PhD, discusses preliminary results from a phase 1 trial of a CD22-directed CAR-T therapy in relapsed/refractory large B-cell lymphoma.
 


Dr Frank on the Initial Efficacy and Safety of CAR22 in Relapsed/Refractory LBCL

Matthew Frank, MD, PhD, assistant professor, medicine, the Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, discusses the rationale for investigating CD22-directed CAR-T cell therapy (CAR 22) in adult patients with large B-cell lymphoma (LBCL) who relapsed after or were refractory to CD19-directed CAR T-cell therapy.

A phase 1 trial (NCT04088890) investigated autologous CAR 22 in evaluable patients, including those who relapsed after or are refractory to CD19-directed CAR T-cell therapy. Findings presented at the 2023 Transplantation and Cellular Therapy Meetings showed that CAR 22 elicited an overall response rate (ORR) of 68%, including ORRs of 66% at dose level 1 of 1 x 106 CAR+ cells/kg and 78% at dose level 2 of 3 x 106 CAR+ cells/kg. The complete response rate was 53% in all patients, 52% at dose level 1, and 56% at dose level 2.

Although 3 CD19-directed CAR T-cell therapies have been approved by the FDA for patients with LBCL, including tisagenlecleucel (Kymriah), lisocabtagene maraleucel (liso-cel; Breyanzi), and axicabtagene ciloleucel (axi-cel; Yescarta), relapsed following those treatments remains an issue for patients, Frank adds.

A major reason for relapse is down regulation or loss of the target, CD19. Therefore, investigators pursued treatment for patients who have relapsed by targeting a different antigen on their tumor, Frank notes. CD22 is expressed in the majority of LBCLs and other malignancies, Frank says.

CD22-directed CAR T-cell therapy had previously displayed efficacy in pediatric patients with leukemia, Frank says, adding that these children were predominantly treated with allogeneic stem cell transplant or CD19-directed CAR T-cell therapy, but had relapsed. This led investigators to design a clinical trial for adult patients with LBCL who predominately relapsed after CD19 CAR T-cell therapy, Frank concluded.

Editor's Note: Dr Frank reports participation on scientific advisory boards for Adaptive Biotechnologies, Kite-Gilead, and Cargo; and industry-contracted research for Allogene Therapeutics, Adaptive Biotechnologies, and Kite-Gilead.

Matthew Frank, MD, PhD, discusses the rationale for investigating CD22-directed CAR-T cell therapy in adult patients with large B-cell lymphoma who relapsed after or were refractory to CD19-directed CAR T-cell therapy.

Dr. Frank on the Rationale for CD22-Targeted CAR T-cell Therapy After CD19 Relapse in LBCL

Matthew Frank, MD, PhD, assistant professor, medicine, the Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, discusses findings from a single-institution phase 1 trial (NCT04088890) investigating autologous CAR T cells targeting CD22 (CAR 22) in adults with large B-cell lymphoma (LBCL), including those who relapse after or are refractory to CD19-directed CAR T-cell therapy (CAR19).

After lymphodepletion with fludarabine and cyclophosphamide, 38 patients with LBCL received CAR22 at 1 of 2 dose levels. Dose level 1 consisted of CAR22 at 1 x 10

 CAR+ cells/kg (n = 29). Dose level 2 consisted of CAR22 at 3 x 10

 CAR+ cells/kg (n = 9). The investigators determined dose level 1 to be the recommended phase 2 dose.

Patients had a median age of 65 years and a median of 4 prior lines of therapy. Notably, 97% (n = 37) of patients had progressed on prior CAR19. The primary end points of this trial were successful CAR22 manufacturing and safety. Secondary end points included efficacy and durability of responses.

Dr. Frank on Response Rates With CD22 CAR T-cell Therapy in Relapsed LBCL

Across both dose levels, the overall response rate (ORR) was 68%, including ORRs of 66% at dose level 1 and 78% at dose level 2, Frank says. The complete response (CR) rate was 53% in all patients, 52% at dose level 1, and 56% at dose level 2, Frank explains. These ORR and CR rates were much higher than the expected outcomes of this trial, Frank notes.

Dr. Frank on the Durability of Responses With CD22 CAR T-cell Therapy

Many of the CRs seen with CAR22 were also durable. At a median follow-up of 18.4 months, of the 20 patients who achieved a CR, 19 had durable remissions, Frank emphasizes. These data support CAR22 as a potentially curative option for patients with LBCL who have relapsed following CAR19, Frank concludes.

 Dr. Frank reports participation on scientific advisory boards for Adaptive Biotechnologies, Kite-Gilead, and Cargo; and industry-contracted research for Allogene Therapeutics, Adaptive Biotechnologies, and Kite-Gilead.

Matthew Frank, MD, PhD, discusses findings from a single-institution phase 1 trial investigating autologous CAR T cells targeting CD22 in adults with large B-cell lymphoma, including those who relapse after or are refractory to CD19-directed CAR T-cell therapy.

Matthew Frank, MD, PhD

Articles

Dr Frank on the Background of Investigating CAR22 Therapy in Relapsed/Refractory LBCL

Dr Frank on Sequencing Questions With CAR22 in Relapsed/Refractory LBCL

Dr Frank on the Initial Efficacy and Safety of CAR22 in Relapsed/Refractory LBCL

Dr. Frank on the Rationale for CD22-Targeted CAR T-cell Therapy After CD19 Relapse in LBCL

Dr. Frank on CD22 CAR T-cell Therapy in Relapsed LBCL