Vaccination with folate receptor-alpha peptides in patients with ovarian cancer following response to platinum-based therapy: A randomized, multicenter clinical trial.

OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.

A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers.

Background: The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T½), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (FHAB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted. Methods: SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101. Results: Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines. Conclusion: SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients. Clinical trial registration: https://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.

SON-1210 - a novel bifunctional IL-12 / IL-15 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy.

Background: The potential synergy between interleukin-12 (IL-12) and IL-15 holds promise for more effective solid tumor immunotherapy. Nevertheless, previous clinical trials involving therapeutic cytokines have encountered obstacles such as short pharmacokinetics, limited tumor microenvironment (TME) targeting, and substantial systemic toxicity. Methods: To address these challenges, we fused single-chain human IL-12 and native human IL-15 in cis onto a fully human albumin binding (FHAB) domain single-chain antibody fragment (scFv). This novel fusion protein, IL12-FHAB-IL15 (SON-1210), is anticipated to amplify the therapeutic impact of interleukins and combination immunotherapies in human TME. The molecule was studied in vitro and in animal models to assess its pharmacokinetics, potency, functional characteristics, safety, immune response, and efficacy. Results: SON-1210 demonstrated robust binding affinity to albumin and exhibited the anticipated in vitro activity and tumor model efficacy that might be expected based on decades of research on native IL-12 and IL-15. Notably, in the B16F10 melanoma model (a non-immunogenic, relatively "cold" tumor), the murine counterpart of the construct, which had mouse (m) and human (h) cytokine sequences for the respective payloads (mIL12-FHAB-hIL15), outperformed equimolar doses of the co-administered native cytokines in a dose-dependent manner. A single dose caused a marked reduction in tumor growth that was concomitant with increased IFNγ levels; increased Th1, CTL, and activated NK cells; a shift in macrophages from the M2 to M1 phenotype; and a reduction in Treg cells. In addition, a repeat-dose non-human primate (NHP) toxicology study displayed excellent tolerability up to 62.5 µg/kg of SON-1210 administered three times, which was accompanied by the anticipated increases in IFNγ levels. Toxicokinetic analyses showed sustained serum levels of SON-1210, using a sandwich ELISA with anti-IL-15 for capture and biotinylated anti-IL-12 for detection, along with sustained IFNγ levels, indicating prolonged kinetics and biological activity. Conclusion: Collectively, these findings support the suitability of SON-1210 for patient trials in terms of activity, efficacy, and safety, offering a promising opportunity for solid tumor immunotherapy. Linking cytokine payloads to a fully human albumin binding domain provides an indirect opportunity to target the TME using potent cytokines in cis that can redirect the immune response and control tumor growth.