Abstract Details

I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

First in Human Studies Show Activation of SC-DARIC33, a Rapamycin-Regulated Anti-CD33 CAR T Cell Therapy, in Patients with AML

Type: Oral Abstract Session

Presentation Details

Session Title: Late-breaking Abstracts 2
Location: Concourse Hall 152 & 153
Start Time: 5/19/2023 11:30
End Time: 5/19/2023 11:45

BACKGROUND: Dimerizing Agent Regulated ImmunoReceptor Complexes (DARICs) are next-generation CARs comprised of separate antigen binding and signaling subunits. DARICs remain inactive until administration of rapamycin (RAPA) results in subunit dimerization, and enables antigen-dependent T cell activation. Modulating CAR T cell activity may aid hematopoietic recovery, enhance CAR T cell function and persistence, and mitigate toxicity. We developed a novel anti-AML T cell therapy, SC-DARIC33, that couples the DARIC technology with a novel humanized nanobody targeting the C2 membrane proximal domain of CD33, a prototypical AML target.
RESULTS: Here we describe preliminary correlative studies from an ongoing first in human phase I trial, PLAT-08 (NCT05105152), evaluating the safety and tolerability of SC-DARIC33. Eligible patients are ≤ 30 years in 1st early relapse (< 6 months), 1st relapse refractory to reinduction, or ≥2nd relapse. Following lymphodepletion (LD) with fludarabine/cyclophosphamide, patients received SC-DARIC33 T cells on day 0 followed by RAPA on days 2-21, targeting trough levels of 1.5-3ng/mL to activate SC-DARIC33. Secondary objectives include assessments of efficacy, engraftment, expansion, persistence, and SC-DARIC33 activation states. Correlative analysis is performed on peripheral blood obtained on days -1, +1, 3, 7, 10, 14, 21, 23, 25, and 28 and optionally at times of suspected T cell mediated toxicity, as well as bone marrow obtained prior to LD, day +14 and +28. At the time of data cut off, 3 patients had received LD and SC-DARIC33 therapy at dose level 1 (1 x 10⁶ SC-DARIC33 T cells/kg). Infusions were well tolerated without occurrence of dose limiting toxicities. Two subjects had whole blood RAPA trough levels above 1.5 ng/mL. Expansion of SC-DARIC33 was noted only in the two subjects who obtained RAPA trough levels in the goal range. The frequency of SC-DARIC33 among T cells peaked on day+13 at 1.8% (PL08-S002) and on day +9 at 6.1% (PL08-S004). Patient PL08-S002 had several chloromas, some of which became inflamed and then involuted. Analysis of a chloroma noted accumulation of SC-DARIC33 compared with peripheral blood (9.95% v 1.8%), indicating trafficking of SC-DARIC33 T cells to areas of disease. Expression of T cell activation responsive markers including PD1, CD137 and TIM3 were increased among DARIC+ T cells in the peripheral blood as well as the chloroma. Patient PL08-S004 exhibited noted expansion of the SC-DARIC33 population in the peripheral blood and simultaneous elimination of the side-scatter low, CD33+ population corresponding to the blast population.
CONCLUSION: These results demonstrate successful RAPA regulated activation of SC-DARIC33 T cells in patients, resulting in expansion and concurrent anti-CD33 activity. PLAT-08 enrollment is ongoing with plans for evaluation of two additional dose levels (5 and 10 x 106 SC-DARIC33 T cells/kg). Future work will focus on understanding SC-DARIC33 T cell activation dynamics following RAPA withdrawal.

Jacob Appelbaum¹, Todd Cooper², Colleen Annesley², Adam Lamble², Stephanie Rhea³, Sowmya Pattabhi³, Joshua A. Gustafson⁴, April Price⁵, Paula Lewis⁵, Scott Currence⁶, Sumati Sundaram⁶, Alexander Astrakhan⁵, Mark Pogson⁵, Jordan Jarjour⁵, Michael C. Jensen⁴, Rebecca Gardner<sup>2

1</sup>University of Washington, Seattle, WA,²Pediatrics, University of Washington, Seattle, WA,³Seattle Childrens Research Institute, Seattle, WA,⁴Seattle Children's Research Institute, Seattle, WA,⁵2seventy Bio, Seattle, WA,⁶2seventy Bio, Cambridge, MA
 J. Appelbaum: None.