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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 Gardner2

1University 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.

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