A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint

Clin Epigenetics. 2021 Feb 2;13(1):25. doi: 10.1186/s13148-021-01014-8.

Abstract

Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3-4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.

Keywords: Colorectal cancer; Epigenetic therapy; GVAX; Immunotherapy.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Azacitidine / administration & dosage
  • Azacitidine / adverse effects
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Biopsy
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology
  • Combined Modality Therapy / methods
  • DNA (Cytosine-5-)-Methyltransferase 1 / antagonists & inhibitors*
  • DNA Methylation / drug effects
  • Epigenomics / methods
  • Feasibility Studies
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Immunotherapy / methods
  • Immunotherapy, Active / methods
  • Leukocyte Common Antigens / drug effects
  • Leukocyte Common Antigens / metabolism
  • Male
  • Middle Aged
  • Safety
  • Severity of Illness Index
  • Tumor Microenvironment

Substances

  • Cancer Vaccines
  • GVAX vaccine
  • guadecitabine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • Leukocyte Common Antigens
  • Azacitidine

Associated data

  • ClinicalTrials.gov/NCT01966289