Clinical Study of Novel Therapeutic Vaccine for Advanced Solid Tumors

Safety, Tolerability, and Preliminary Antitumor Activity of Novel Therapeutic Tumor Vaccines in Advanced Solid Tumors

Advanced solid tumors remain a major therapeutic challenge due to their complex heterogeneity and the immunosuppressive tumor microenvironment (TME). Although cancer vaccines are designed to induce long-lasting antitumor immunity, their efficacy is often limited by the TME's immune-evasive mechanisms.

Building on this rationale, investigators developed a novel vaccine comprising irradiated tumor cells and stromal cells isolated from adjacent non-cancerous tissues or tumor tissues in combination with adjuvant. Irradiated tumor cells in vaccines such as YMN102, YMN103, YMN104, YMN105, YMN106, and YMN107 are transfected with GM-CSF; the others, such as YMN101 and YMN108, are not transfected with GM-CSF. Preclinical studies across multiple tumor models have demonstrated potent antitumor activity with no significant toxicity observed following administration. This first-in-human Phase I study is designed to evaluate the safety and tolerability of this irradiated vaccine in patients with advanced solid tumors, alongside a preliminary assessment of its antitumor activity and immunogenic profile.

This is a first-in-human, Phase I, open-label study designed to evaluate the safety and tolerability of this novel vaccine. The study includes multiple arms targeting specific malignancies, including osteosarcoma, pancreatic cancer, HNSCC, colorectal cancer, HCC, glioma, and TNBC.

The primary objective is to determine the incidence of dose-limiting toxicities (DLTs). Secondary objectives include assessing the objective response, progression-free survival (PFS), and overall survival (OS) per RECIST v1.1. Exploratory analyses will monitor dynamic changes in circulating biomarkers and intratumoral immune modulation to identify potential predictive markers of clinical response.

Whole tumor cell-based vaccines provide a broad spectrum of tumor-associated antigens; however, their clinical utility is frequently limited by low intrinsic immunogenicity and an inability to overcome the immunosuppressive tumor microenvironment (TME). These limitations underscore the urgent need for strategies that can simultaneously enhance antigen presentation and modulate TME-mediated immune evasion.

The TME plays a pivotal role in shaping antitumor immunity. Non-malignant cellular components within the TME not only contribute to immune regulation and tumor progression but also interact dynamically with tumor-associated antigens. Leveraging these interactions may offer a unique opportunity to potentiate immune activation and improve vaccine efficacy.

Building on this rationale, investigators developed a novel vaccine comprising irradiated tumor cells and stromal cells isolated from adjacent non-cancerous tissues or tumor tissues in combination with adjuvant. Irradiated tumor cells in vaccines such as YMN102, YMN103, YMN104, YMN105, YMN106, and YMN107 are transfected with GM-CSF; the others, such as YMN101 and YMN108, are not transfected with GM-CSF. Preclinical studies across multiple tumor models have demonstrated potent antitumor activity with no significant toxicities observed following administration. This first-in-human Phase I study is designed to evaluate the safety and tolerability of this irradiated vaccine in patients with advanced solid tumors, alongside a preliminary assessment of its antitumor activity and immunogenic profile.

Inclusion Criteria

1. Histologically or cytologically confirmed advanced solid tumors, or radiologically diagnosed HCC, eligible for one of the following study parts based on tumor type, clinical status, and prior treatment history:

   Part A1: Patients with advanced osteosarcoma who achieved Stable Disease (SD) or Partial Response (PR) following first-line chemotherapy, and have at least one remaining lung metastatic lesion >= 0.5 cm.

   Part A2: Patients with advanced osteosarcoma who have relapsed, metastasized, or progressed following prior chemotherapy, or who are intolerant to the toxicities of previous systemic therapy.

   Part B1: Patients with advanced pancreatic cancer and disease progression following >= 1 prior line of standard systemic therapy.

   Part C1: Patients with advanced HNSCC and disease progression following >= 2 prior lines of systemic therapy.

   Part D1: Patients with advanced colon cancer and disease progression following >= 3 prior lines of therapy (including fluoropyrimidine, oxaliplatin, and irinotecan). Patients with RAS wild-type must have received EGFR inhibitors.

   Part E1: Patients with advanced hepatocellular carcinoma (HCC) and disease progression following >= 2 prior lines of systemic therapy.

   Part F1: Patients with advanced glioma and disease progression following the first-line Stupp regimen.

   Part G1: Patients with advanced pancreatic cancer and disease progression following >= 1 prior line of therapy.

   Part H1: Patients with advanced or recurrent metastatic breast cancer who have progressed on or after >= 3 prior lines of systemic therapy.

2. Age 18-75 years.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

4. Life expectancy > 3 months.

5. Adequate organ function within 7 days prior to first dose, including:

   Hematologic: Hemoglobin (Hb) >= 80 g/L; White Blood Cell count (WBC) >= 3.0 x 10^9/L; Platelet count (PLT) >= 80 x 10^9/L; Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L.

   Hepatic: Total bilirubin <= 1.5 x ULN (<= 3 x ULN for liver metastases or HCC); ALT and AST <= 2.5 x ULN (<= 5 x ULN for liver metastases or HCC).

   Renal: Creatinine clearance > 60 mL/min (Cockcroft-Gault formula). Coagulation: International Normalized Ratio (INR) <= 1.5 x ULN.

6. At least one measurable or evaluable lesion per RECIST v1.1.

7. Ability to understand and sign written informed consent and comply with study procedures.

Exclusion Criteria

1. Another primary malignancy within 5 years prior to first dose, except for adequately treated non-melanoma skin cancer, carcinoma in situ, or localized low-risk cancers.
2. Active central nervous system (CNS) metastases or leptomeningeal disease.
3. Positive for infectious diseases, including HIV, active Hepatitis C (HCV RNA positive), or active Hepatitis B (HBsAg or HBcAb positive with HBV DNA >= 500 IU/mL or >= 2000 copies/mL).
4. Active pulmonary tuberculosis.
5. Active autoimmune disease requiring systemic treatment within the past 2 years; or use of systemic corticosteroids (> 10 mg/day prednisone equivalent) within 4 weeks prior to first dose.
6. Major surgery or significant trauma within 28 days prior to enrollment, or presence of unhealed wounds, ulcers, or conditions associated with high risk of bleeding or perforation.
7. Arterial/venous thrombosis or pulmonary embolism within 6 months, or CTCAE Grade >= 3 bleeding event within 28 days prior to treatment.
8. Localized conditions at the injection site (e.g., infection, inflammation, or extensive scarring) or clinically significant coagulation disorders that contraindicate subcutaneous or intraosseous administration.
9. Known hypersensitivity or intolerance to study treatment components or related compounds.
10. Pregnant or breastfeeding, or planning to conceive (participant or partner) during the study.
11. Any condition that, in the investigator's judgment, may compromise safety or interfere with study participation or evaluation.