A Phase 1 Study to Evaluate the Safety and Tolerability of a Combination Autologous CD19 CAR T Cell Therapy (SYNCAR-001) and Orthogonal IL-2 (STK-009) in Subjects with Relapsed or Refractory CD19 Expressing Hematologic Malignancies (NCT05665062)
Authors: Palomba Maria Lia , Caimi Paolo F. , Mei Matthew , Hernandez-Ilizaliturri Francisco , Shouse Geoffrey , Winter Allison M. , Yedinak Greg , Mou David , Huang Nestor , Moua Anna , Oft Martin , Aspuria Paul-Joseph , Mehta-Damani Anita , Rizvi Naiyer , Unabia Sherry , Taylor Peg , McLeroy Jeffrey , Cortese Matthew J 
Published: December 2024

Background:
CAR T cell therapy has demonstrated clinical efficacy in hematologic malignancies. However, their efficacy can be limited by compromised T cell effector function, proliferation, and persistence. Interleukin (IL)-2 is a potent T cell stimulator, but its therapeutic application is limited by toxicity. To provide a selective IL-2 signal, we developed a human orthogonal ligand/receptor system for cell therapy. SYNCAR-001 is an autologous CAR T cell co-expressing a CD19-28z CAR and a mutated IL-2 receptor beta (hoRβ). SYNCAR-001 is administered with STK-009, a pegylated IL-2 mutein that provides a selective IL-2 signal to hoRβ. Preclinically, STK-009 expanded and sustained SYNCAR-001 as stem cell memory and effector T cells, resulting in complete and durable responses in refractory lymphoma. We report initial data investigating the combination of SYNCAR-001 + STK-009 (STK-009-101) in adults with relapsed or refractory (r/r) mature CD19+ hematologic malignancies.
Methods:
STK-009-101 is a first in human, dose escalation study in adults with r/r mature CD19+ hematologic malignancies. The objectives of the study are to evaluate the safety, efficacy, immunogenicity, and PK/PD of SYNCAR-001 + STK-009 with or without lymphodepleting chemotherapy (LDC; cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day on Day -5 to Day -3). Dose escalation follows a 3+3 design with STK-009 escalated in 4 dose levels (1.5, 3, 6 and 12 mg) while SYNCAR-001 is a fixed flat dose (Cohort A [with LDC] = 30×106 cells; Cohort B [without LDC] = 90×106 cells). SYNCAR-001 is dosed IV once on Day 0 and STK-009 is dosed SC over the course of the study. STK-009 is administered once 10 to 18 days before Day 0 (safety lead-in), weekly x 12, then monthly x 3. Eligible indications included CLL/SLL, LBCL, MCL, FL and MZL. Prior treatment with CD19-targeting CAR T cells is excluded. AEs were graded by CTCAE v5.0 and CRS and ICANS were graded using ASTCT criteria.
Results:
As of 18 June 2024, 6 subjects in Cohort A (2 dose levels) received SYNCAR-001 + STK-009 (3 subjects at 1.5mg; 3 subjects at 3mg) and were followed for at least 28 days. Enrollment into Cohort B was recently initiated, and no subjects were treated at time of submission. The median age was 62.5 (range: 56 -70). Indications: 3 CLL, 2 MZL and 1 DLBCL. Median prior therapies were 4 (range: 2-5) and 4 subjects received bridging therapy. All CLL subjects had high risk features, including IGHV unmutated and del(17p), as well as an elevated baseline LDH, median of 705 (range 501 - 996). DLBCL IHC demonstrated: C-MYC 20%, co-expression of BCL-2/BCL-6 and a Ki67 of 90%. BCL-2 rearrangement was identified by FISH.
The majority of reported AEs were low grade (≤ Grade 2) and non-serious. No DLTs were observed and only 2 of the 11 SAEs reported were considered related to either SYNCAR-001 or STK-009. CRS occurred in 2 subjects (max Grade 2) and ICANS (max Grade 1) occurred in 1 subject (the DLBCL subject experienced both CRS and ICANS). Four subjects had no CRS or ICANS (MZL subjects and 2 CLL subjects). STK-009 alone did not induce IL-2 related biomarkers or IFNγ and no cytokine-related AEs were observed during the safety lead-in period.
All 3 NHL subjects are in ongoing CR. The 2 MZL subjects are in ongoing CR for 180+ and 270+ days. The DLBCL subject achieved CR after bridging therapy and remains in CR for 90+ days. The 3 CLL subjects experienced PD by Day 28 (1 subject had Richter's transformation on Day 16).
STK-009 exhibited a half-life of 4 days and a dose dependent serum exposure up to 773ng/mL, exceeding its EC50. STK-009 was maintained at high serum levels throughout the dosing period. STK-009 mediated SYNCAR-001 expansion and B cell aplasia were observed, even in subjects with low LDC induced IL-15. Active SYNCAR-001 cells persisted in the blood for 9+ months after infusion. STK-009 induced and maintained a SYNCAR-001 phenotype of more than 90% non-exhausted (TIM3-) and non-senescent (CD27/CD28+) SYNCAR-001 cells. STK-009 + SYNCAR-001 also preferentially induced IFNγ (median peak: 200pg/mL) with limited elevation in IL-6 (median peak: 17pg/mL).
Conclusions:
This is the first reported clinical and translational data of an orthogonal cytokine system that provides a selective IL-2 signal to CAR T cells. Early results show that STK-009 administered with only 30×106 SYNCAR-001 CAR T cells has a favorable safety profile, durable efficacy, and meaningful SYNCAR-001 fitness, expansion and persistence.