Clinical trial NCT05767684: Neoantigen Derived DCs as Cancer Treatment
Official title: Personalized Neoantigen Derived Dendritic Cell-Based Immunotherapy as Cancer Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Refractory Tumor
Solid Tumor
Keywords: immunotherapy
cancer vaccine
neoantigen
Lead sponsor: National Health Research Institutes, Taiwan
Sponsor class: OTHER
Collaborators: name: National Cheng-Kung University Hospital
First posted: 2023-03-14
Enrollment: 12
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All patient will receive DCs monotherapy initially on day 1, 8, 15 and 29 as safety run-in. Safety and efficacy (1st CT evaluation) will be conducted at day 43. On the 1st CT evaluation, patient met randomization criteria and without progression disease/safety concern will be randomized to either observation or booster of lenvatinib and nivolumab during day 43 to 77.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of subjects experienced limiting toxicities in the first 6 weeks.
timeFrame: 6 weeks
Secondary outcomes:
measure: Percentage of patients who had a clinical response
timeFrame: 1 year
measure: Number of participants who did not progressed or survived at 1 year
timeFrame: 1 year
measure: Number of subjects experienced any ≥ grade 3 toxicities.
timeFrame: 1 year
Other outcomes:
measure: Number of subjects experienced immune response
timeFrame: 1 year
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Tainan
country: Taiwan
facility: National Cheng-Kung University Hospital
city: Tainan
country: Taiwan
facility: National Institute of Cancer Research
Study officials:
affiliation: Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University
name: Li-Tzong Chen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: