Title : Development of nanobody-armored DC vaccine (BaizeDC) and its preliminary exploration in preventing solid tumor recurrence
Abstract:
Background: Dendritic cells (DCs) are pivotal in developing therapeutic cancer vaccine based on its function of crossing antigen presenting and induction of anti-tumor cytotoxic T lymphocyte response.1,2 To increase the efficacy of current anti-tumor DC vaccine, we developed a bi-specific anti-PD-1/CTLA-4 nanobody-armored DCs (BaizeDC) expressing tumor associated antigens (TAAs) p53 and Survivin. PD-1 and CTLA-4 are established immune checkpoints, p53 and Survivin are TAAs widely expressed in various solid tumors. The combination of immune checkpoint inhibition and TAA-specific T cell stimulation is expected to improve clinical response3. A first-in-human study was initiated to explore the pharmacokinetics (PK), safety and preliminary efficacy of this novel DC vaccine.
Methods: In vitro synthesized mRNA encoding TAAs and anti-PD-1/CTLA-4 Tiniplasmid were electroporated into mature DCs induced from monocytes. DC viability and recovery, phenotype and migration efficacy were measured once thawed after 10-day cryopreserve. 24 hours post recovery, antigen expression, nanobody level and pro-inflammatory cytokines of DCs were analyzed. IFN-γ and activated T cell surface markers were tested after co-culturing DCs and autologous T cells for 3 days. A single-arm, open-label, early phaseI study approved by the Institutional Review Board was conducted in Shanghai Mengchao Cancer Hospital (NCT06015269). Subjects meeting the inclusion and exclusion criteria and signing the informed consent were enrolled in the study. Total 8 doses were intradermally injected to patients with 1E7 DCs each dose on Day0, 7, 14, 21 and Month2, 3, 4 and 5. Adverse events (AEs) were monitored throughout study. PK of anti- PD-1/CTLA-4 nanobody were tested on Day0, 1, 3, 5, 7, 28 and immune response was examined on Day0, Month2 and 3 by TAA-specific T cell response. Preliminary efficacy was assessed by disease free survival.
Results: The thawed DCs exhibited a purity of >90% and viability of >80%. More than 90% BaizeDC expressed co- stimulation molecules CD80, CD86, maturation marker CD40, HLA-ABC and chemokine receptor CCR7. The expression of Survivin, p53 and antiPD-1/CTLA-4 nanobody was 1.65ng/mL, 15.8 ng/mL 138.6 ng/mL respectively. TNF-a and IL-12 secretion by DCs exceeded 200 pg/mL. T cells activation by BaizeDC was evidenced by an IFN-γ level of 1563.45 pg/mL, surface marker analysis revealed CD69 positivity in 40% CD4+ and 20% CD8+ T cells, CD25 positivity in 40% and 60% of CD4+ and CD8+T cells.Four patients with a median age of 44 years post-solid tumor resection were enrolled in the clinical study. Anti-PD-1/CTLA-4 nanobody increased rapidly on Day1 with Cmax 6pg/mL and remained detectable until Day28. The most common AEs were injection site induration, no grade II or higher treatment-emergent adverse events happened. TAA- specific T cell response was detected in 3/4 patients with strongest immune reaction at Month2 or 3. There was no tumor recurrence identified with a median 8.6 months follow-up.
Conclusion: Autologous BaizeDC expressing p53 and Survivin armed with bispecific anti-PD-1/CTLA-4 nanobody enables to activate T cells in vitro. It is safe in multiple injections and provokes T cell specific responses in human. The effectiveness of BaizeDC in preventing cancer recurrence or metastasis requires continuing follow-up and involving more subjects.
Audience Take Away:
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The audience will gain insights into the innovative approach of integrating immune checkpoints inhibition with anti-tumor T cell activation stimulation in the design and development of therapeutic cancer vaccine
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Meeting participants will be informed about the pioneering observations of anti-PD-1/CTLA-4 nanobody in humans, persisting for an average duration of 7 days, with the longest recorded presence lasting up to 28 days post-administration of therapeutic dendritic cell (DC) vaccines
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The audience will be presented with findings from a first-in-human clinical trial that evaluated the safety and effectiveness of the novel vaccine in preventing the recurrence of tumors
