Neoantigen Derived DCs as Cancer Treatment

National Health Research Institutes, Taiwan

Status and phase: Enrolling; Phase 1

Conditions: Solid Tumor; Refractory Tumor

Treatments: Drug: Lenvatinib; Drug: Nivolumab; Biological: Dendritic Cell Vaccine

Study type: Interventional

Funder types: Other

Identifiers

NCT05767684

A-BR-108-087

Details and patient eligibility

About

Tumor lysate or carcinoembryonic antigen (CEA) derived DCs-based therapy is safe and can elicites remarkable T-cell responses but mostly did not really transfer into significant clinical benefit. One possible reason is the lack of effective antigen and the immunosuppressive microenvironment. Now we are exploring another new strategy, prediction of neoantigen for priming DCs as cell-based therapy with or without booster of anti-VEGF/anti-PD-1.

Full description

The human immune system can recognize and destroy cancer cells but cancer cells are capable of escaping from immune system by different ways, including the PD-1/PDL-1 axis and the VEGF signaling pathway. The PD-1/PD-L1 axis represents an adaptive immune resistance mechanism exerted by tumor cells. Previous study also revealed VEGF-A could induce tumor-associated macrophages, Treg cells, and myeloid-derived suppressor cells, creating an immunosuppressive microenvironment that prevent the maturation of dendritic cells (DCs) and inhibit the activation of NK cells and T cells. Our research group already completed some early phase clinical trials of DCs-based therapy, which illustrated tumor lysate or carcinoembryonic antigen (CEA) derived DCs-based therapy is feasible and safe in patients with advanced colorectal cancer and lung cancer, respectively. However, although DCs-based therapy elicited remarkable T-cell responses but mostly did not really transfer into significant clinical benefit in previous study. One possible reason is the lack of effective antigen and the immunosuppressive microenvironment. Now we are exploring another new strategy, prediction of neoantigen for priming DCs as cell-based therapy with or without booster of anti-VEGF/anti-PD-1.

Enrollment: 12 estimated patients

Sex: All

Ages: 20+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• ≥20 years of age

• Provide written informed consent

• Histologically confirmed stage IV pancreatic cancer, liver cancer, biliary tract cancer and colorectal cancer (excluding sarcoma and neuroendocrine tumor) that refractory or intolerance to standard therapies for their condition (there is no effective treatment by investigator judgement)

• Completed tumor and germline DNA and RNA sequencing and the neoantigen prediction

• Patients with chronic hepatitis B is eligible if receiving anti-hepatitis B agents and the HBV DNA level < 2000 IU/ml prior to the preparation phase. Patients with chronic hepatitis C are eligible if HCV RNA is undetectable (<15 IU/ml) prior to the preparation phase

• Adequate organ function

  • Absolute neutrophil count >1000/mcL
  • Hemoglobin > 8.0 g/dl
  • Platelet > 50000/mcL
  • PT/aPTT < 1.5 x upper limit of normal (ULN)
  • AST/ALT < 3 x ULN
  • Bil(T) < 1.5 x ULN
  • BUN/Cr < 1.5 x ULN

• Adequate immune system as defined by

  • IgG > 614 mg/dl
  • IgM > 53mg/dl

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2

• Life expectancy at least>12weeks

• At least one measurable target lesion as defined by RECIST 1.1

Exclusion criteria

• Sarcoma、neuroendocrine tumor
• Last anticancer therapy administered within 2 weeks and any AEs should be ≤ grade 2 prior to leukapheresis
• Patients who cannot tolerate leukapheresis and follow-up blood sampling of 50ml at day 43, day 85 and end-of- treatment.
• Any known active infection as judged by the investigator
• Any known chronic active infection of HIV, HTLV-1 or HTLV-2
• Requirement of systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to the screen phase. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Other immunocompromising condition that in the opinion of the treating physician renders the patient a poor candidate for this trial
• Pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device (IUD), abstinence, etc.)
• Patients with history of penicillin allergy
• Other medical problems or conditions that, in the opinion of the investigator, would make participation in the study hazardous for the patient

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

12 participants in 2 patient groups

Arm 1: DCs monotherapy

Experimental group

Description:

DCs injection on day 1, 8, 15, 29, 85, 141, 197, 253 and 309.

Treatment:

Biological: Dendritic Cell Vaccine

Arm 2: DCs with booster of anti-VEGF/anti-PD-1.

Experimental group

Description:

DCs injection on day 1, 8, 15, 29, 85, 141, 197, 253 and 309 plus lenvatinib 10mg QD on day 43-77 and nivolumab 3mg/kg on day 43, 57 and 71.

Treatment:

Biological: Dendritic Cell Vaccine

Drug: Nivolumab

Drug: Lenvatinib