SYNC-T Therapy SV-102 Shows Early Promise, Advances to Phase 2 LEGION-100 Trial in Refractory Prostate Cancer

SYNC-T Therapy SV-102, an experimental in-situ immunotherapy, is designed to generate tumor-specific T-cell responses in androgen pathway modulation–refractory prostate cancer and will be evaluated in the phase 2 LEGION-100 study (NCT06533644) following positive data from a phase 1 study (NCT05544227), according to Leonard J. Appleman, MD, PhD.

“There remains an unmet need in metastatic prostate cancer even with all the newer agents available,” Appleman, section chief of genitourinary medical oncology at UPMC Hillman Cancer Center, director of the Genitourinary Cancer Disease Sectionand associate professor of medicine at the University of Pittsburgh in Pennsylvania, said in an interview with OncLive®. “Nearly every patient's cancer eventually becomes androgen pathway refractory, and those patients generally can't be cured. They become resistant to subsequent therapies such as radioligand therapy, chemotherapy, and others. We don't currently have the ability to achieve durable cancer control in that setting.”

In the interview, Appleman discussed the mechanism of SYNC-T Therapy SV-102, efficacy and safety data from the phase 1 study, the design of LEGION-100, and where the agent could fit into the prostate cancer treatment paradigm if data continue to read out positively.

OncLive: Please describe what SYNC-T Therapy SV-102 is, how it works, and what differentiates it from currently available therapies in this space.

Appleman: This is an experimental approach to treating androgen pathway modulation–refractory prostate cancer, [which is] disease that has progressed on androgen deprivation therapy [ADT] plus a second-generation androgen signaling inhibitor. It takes an immunologic approach that functions almost like an in vivo vaccine, eliciting a T-cell immune response against tumor antigens using the tumor in situ as the antigen source.

There's nearly 100 years of literature on this general concept. Going back to at least the 1940s, investigators have removed tumors and processed them ex vivo—freeze-thawing them, mixing them with different adjuvants—to generate immunity in animal models, and clinical trials using similar approaches date back to at least the 1960s. SYNC-T Therapy SV-102 is different in that the entire process happens in situ.

The first component is limited cryolysis of a portion of the tumor. An area of cancer is identified on imaging, a cryoprobe is introduced into the tumor, and a limited area is treated with cryolysis. The goal isn't to ablate the entire lesion the way interventional radiologists use cryotherapy as a standalone treatment, but to create a zone of cryolysis that generates a systemic effect. We believe the cryolysis induces necrotic cell death, essentially breaking cells open by brute force, whether through heat, freezing, mechanical stress, or a cell outstripping its growth. That's distinct from apoptotic cell death, which is a more orderly, programmed process in which cells digest their proteins internally rather than releasing them into the extracellular space. Necrotic cell death releases intracellular proteins where they can be taken up by antigen-presenting cells and displayed to T cells.

That cryolysis is then combined with a series of 4 monoclonal antibodies designed to provide stimulatory signals to enhance the immune system and to block inhibitory signals: an anti–PD-1 antibody, an anti–CTLA-4 antibody, a CD40 agonist antibody, and a TLR9 agonist antibody. Published literature shows that limited cryolysis combined with a TLR9 agonist works cooperatively to generate T-cell immunity, recruit antigen-presenting cells, and drive antigen presentation.

In terms of how this differs from existing therapies, the most widely used immunotherapies in cancer right now are immune checkpoint inhibitors, which are given systemically and take the brakes off T cells in a nonspecific way, which is why autoimmunity is seen in many patients. SYNC-T Therapy SV-102, like tumor vaccines and other antigen-specific immunotherapy approaches developed over the years, is trying to generate preferentially tumor-specific T-cell immunity rather than nonspecific systemic T-cell activation.

What data have been shared so far with SYNC-T Therapy SV-102 from the phase 1 study in patients with prostate cancer?

[This study] was presented at the 2025 ASCO Annual Meeting. It was a single-institution study in a similar population as [LEGION-100]. [It included] patients with androgen pathway modulation–refractory prostate cancer and used the same basic experimental protocol of the 4-antibody cocktail plus limited cryolysis.

Fifteen patients were enrolled. All had received prior ADT, and 20% had received prior chemotherapy. By independent review, the overall response rate was 87%, with a complete response rate of 53% [95% CI, 29%-79%]. Additionally, 47% of patients had either a prostate-specific antigen [PSA] reduction greater than 50% or an undetectable PSA throughout treatment, although it's unclear whether that undetectable PSA was present from the start of treatment, which would be harder to interpret.

The regimen was generally well tolerated, without a great deal of high-grade toxicity. Some patients had fever and hematuria; 1 patient had grade 2 hypothyroidism, and 1 had grade 2 hepatitis. Although the 4 antibodies are given as a local infusion into the tumor, there may be some systemic exposure to the checkpoint inhibitors, which is consistent with what was observed in this study. Correlative science showed upregulation of IFN-γ, TNF-α, and IL-6, along with expansion of new T-cell clone frequency. Those data supported initiation of the current multicenter study.

What are the key design characteristics of the phase 2 LEGION-100 study?

The population is similar [to the phase 1 study]. [LEGION-100 is enrolling] patients with androgen receptor pathway–refractory prostate cancer. Some additional prior treatments are allowed, up to a certain extent. The study treatment is also similar to what was used in the study presented at ASCO. It's a larger study open at multiple sites, but the basic objectives are the same: evaluating efficacy and safety.²

Looking ahead, where do you see SYNC-T Therapy SV-102 potentially fitting into the prostate cancer treatment landscape if this study is positive? What unmet needs could it address?

Where SYNC-T Therapy SV-102 would fit in sequence relative to existing and in-development agents is hard to speculate on. In general, immunotherapies tend to work better earlier in the disease course, when there's a lower cancer burden and fewer prior treatments. But with all the new agents and trials in this space, I don't think anybody knows yet where it will ultimately fit.

References

1. Link Jr CJ, Kee S, Prendergast GC, et al. Clinical responses to SYNC-T therapy: in situ personalized cancer vaccination with intratumoral immunotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43(suppl 16):2504. doi:10.1200/JCO.2025.43.16_suppl.2504
2. A study of SYNC-T therapy SV-102 in participants with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated June 23, 2026. Accessed July 29, 2026. https://clinicaltrials.gov/study/NCT06533644