SC-DARIC33 Demonstrates Potential Next-Generation Approach in AML
Data on SC-DARIC33 reinforce the potential of the agent as a new T-cell therapy approach for patients with acute myeloid leukemia.
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Infusions of SC-DARIC33, a chimeric antigen receptor (CAR) T-cell therapy, were well tolerated and did not show dose-limiting toxicities in patients with relapsed or refractory acute myeloid leukemia (AML) according to findings from the preliminary correlative analysis of the ongoing phase 1 PLAT-08 trial (NCT05105152).1
Findings were presented at this year's American Society of Gene & Cell Therapy (ASGCT) Annual Meeting in Los Angeles, California and showed that the combination of regulated IL-15 production and rapamycin-controlled DARIC33 activation enhanced anti-AML potency.
Additionally, the combination demonstrated a potential next generation approach. iSynPro-regulated expression combined with rapamycin-controlled DARIC33 activation may enhance T-cell function while preventing unrestrained T cell outgrowth.
“The treatment of patients with relapsed and refractory AML represents a tremendous unmet medical need, particularly for pediatric and young adult patients. Progressing the promise of CAR T therapy, while mitigating potentially dose-limiting toxicity, has the potential to be a meaningful advance,” said Steven Bernstein, MD, chief medical officer, 2seventy bio, Inc., in the press release. “Together with Seattle Children’s Therapeutics, we are pleased to share results that demonstrate 3 key steps toward clinically meaningful outcomes: rapamycin dosing optimization, rapamycin-regulated in vivo expansion, and activation of SC-DARIC33 T cells as well as concurrent anti-CD33 activity. These data reinforce the potential of SC-DARIC333 as a new T-cell therapy approach in AML.”
SC-DARIC33 is an investigational CD33-CAR T cell therapy that utilizes the proprietary Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T cell platform by 2seventy Bio. Previously, SC-DARIC33 has shown to be activated by low non-immunosuppressive concentrations of rapamycin in the blood. When rapamycin is removed, DARIC returns to an inactive state.
In preclinical studies, investigators predicted that DARIC33 dimerization, activation and expansion would occur at rapamycin trough levels in the range of 1.5-3 ng/ml. These are below the trough levels associated with immune suppression. Now, SC-DARIC33 is being evaluated to determine if a pharmacologically regulated CAR can enable potent AML targeting while limiting toxicities that are linked with normal myeloid and myeloid progenitor cell targeting.
The phase 1 PLAT-08 study evaluating SC-DARIC33 in relapsed/refractory pediatric AML is being led by Seattle Children’s Therapeutics. Enrollment in PLAT-08 is now open and remains ongoing.
Pediatric and young adult patients aged 30 years and younger with relapsed or refractory CD33-positive leukemia with and without prior history of allogeneic hematopoietic cell transplantation are eligible for enrollment. Patients must be in first early relapse (less than 6 months), first relapse refractory to reinduction, or ≥ second relapse. Additional requirements include that patients must tolerate apheresis or be a patient with sufficient existing apheresis products or T cells for manufacturing investigational product, have a life expectancy of 8 weeks, an appropriate stem cell donor source identified, adequate organ function, and a Lansky performance status score of ≥ 50 for subjects <16 years of age or Karnofsky score ≥ 50 for subjects ≥ 16 years.2
After patients received lymphodepletion (LD) with fludarabine/cyclophosphamide, patients were given SC-DARIC33 T cells followed by intermittent oral rapamycin to activate SC-DARIC33.
Primary end points of the study included assessment of safety regarding adverse events, toxicity of SC-DARIC33, and the feasibility of manufacturing. Secondary end points were efficacy, engraftment, expansion, persistence, and activation states of SC-DARIC33 T cells.
By March 17, 2023, there were 3 participants who had received cell product infusion at 1 x 106 SC-DARIC33 T cells /kg, also known as dose level 1, following LD chemotherapy. Among patients, the infusions were generally well tolerated and did not result in dose-limiting toxicities.2
After adjusting rapamycin monitoring and dosing algorithm, rapamycin trough levels in the range of 1.5-3 ng/ml were attained in 2 patients and were associated with DARIC33 dimerization, activation, engagement of antigen and elicitation of CD33 expressing leukemic cell cytotoxicity. Of these 2 patients, the first had extramedullary leukemia. Clinicians were able to infiltrate, activate and expand DARIC33 cells within an extramedullary leukemic infiltrate in the skin, leading to hemorrhagic necrosis of this infiltrate.1
For the second patient, DARIC33 expansion in the peripheral blood was observed 9 days after DARIC33 infusion, and 6.1% of the total lymphocytes were DARIC33 cells. The expansion of DARIC33 was associated with a significant transient reduction in the CD33 leukemic burden in the blood.
When taken together, investigators believe that at this very low cell dose, rapamycin can be dosed to target levels which will result in the activation and expansion of DARICC33 cells. This can then traffic to, engage, and kill leukemia cells.
In another oral presentation at ASGCT, regulated IL-15 production combined with drug-controlled DARIC33 activation was evaluated to determine whether it could enhance anti-AML potency without driving uncontrolled T-cell growth or severe toxicity in the preclinical setting.
Similar expansion and phenotype characteristics were observed with DARIC33 and iSP-IL-15 DARIC33 CAR T cells during initial manufacturing. T-cell activation with tumor cells led to rapamycin-dependent secretion of IL-15 in vitro and robust T-cell expansion. When investigators took IL-15 out of the culture media, iSP-IL-15 DARIC33 showed enhanced expansion following tumor exposure, and normal contraction kinetics. This suggests that iSP transcription may enhance T-cell function through tightly regulated IL-15 production without promoting unrestrained T-cell growth.
Overall, these results demonstrate that Seattle Children’s proprietary iSynPro-regulated expression combined with rapamycin-controlled DARIC33 activation has the potential to enhance T cell function while preventing unrestrained T cell outgrowth.
REFERENCES:
2seventy bio presents late-breaking results for SC-DARIC33, an investigational CD33-targeting CAR T in pediatric and young adults with relapsed or refractory acute myeloid leukemia. News release. May 19, 2023. Accessed May 22, 2023. https://bit.ly/3olxfmC
PLAT-08: A study of SC-DARIC33 CAR T cells in pediatric and young adults with relapsed or refractory CD33+ AML. ClinicalTrials.gov. Updated September 9, 2022. Accessed May 22, 2023. https://clinicaltrials.gov/ct2/show/NCT05105152
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