Whole tumor cell vaccines engineered to secrete GM‐CSF (GVAX)

Abstract

Generation of immunity against cancer through vaccination has long been an elusive goal for tumor immunologists. Putative candidates for vaccination targets include oncofetal antigens, viral antigens, neoantigens, and differentiation antigens. The first attempts at cancer vaccination used injections of whole autologous tumor cells. However, these unmodified tumor cells did not engender a robust immune response. Subsequent efforts were focused at enhancing the immunogenicity of whole autologous tumor cell vaccines through genetic modification, often through virally mediated transduction of genes encoding immunostimulatory molecules. Of many immunostimulatory cytokines evaluated in the context of gene‐modified tumor cell vaccines, granulocyte–macrophage colony‐stimulating factor (GM‐CSF) emerged as the most potent in generating protective antitumor immunity. Vaccination using irradiated, GM‐CSF producing tumor cells (GVAX) consistently induced antitumor immunity across several experimental tumor models. The term GVAX can connote GM‐CSF secreting cell vaccines prepared with different vectors as well as vector targets including autologous tumor cells, allogeneic tumor cell lines, and bystander third party tumor cells lines. GVAX has been evaluated against solid tumors, hematologic malignancies, and in the context of hematopoietic stem cell transplantation. GVAX has been extensively studied in clinical trials, both alone and in conjunction with lymphodepleting chemotherapy, immune checkpoint inhibitors, and other vaccines.

Immortalized human myoblast cell lines for the delivery of therapeutic proteins using encapsulated cell technology

“…Nevertheless, several immortalized cell lines have been clinically tested in immuno-oncology, including the K562 line, a human erythroleukemic cell line that served as the backbone of multiple clinical trials over the last decades without safety concerns. 69 , 70 In addition, the reported cell line is intended to be solely used with macroencapsulation technology, which is a semipermeable macrocapsule. The cells never come into contact with the patient, and the implant can be extracted from the body at all time.…”

Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells

“…The dramatic success of immune checkpoint blockade immunotherapy has revived interest in cancer vaccines, which might provide a complementary means to help eliminate primary and distant tumors and then maintain durable surveillance against recurrence. 28 29 Most recent efforts to increase immunogenicity of lethally irradiated tumor cell vaccines have relied on engineering the cells to express GM-CSF or other cytokines toward promoting antigen uptake and presentation, with several examples under clinical investigation such as GVAX for pancreatic and prostate cancers 30 and Vigil for ovarian cancer. 31 Among many alternative strategies to produce immunogenic whole tumor cell vaccines, preclinical studies have reported encouraging results with early ferroptotic cells, 32 necroptotic cells 33 and etoposide-injured cells.…”

Engineered tumor cell-derived vaccines against cancer: The art of combating poison with poison

“…Whole tumor cell vaccines have attracted attention because they contain the complete antigen spectrum of tumor cells [ 27 , 69 ]. The first attempt at a cancer vaccine in the early 20th century involved the injection of whole autologous tumor cells [ 70 ]. A complete set of autologous antigens includes epitopes recognized by CD8 + CTLs and by CD4 + helper T cells, inducing powerful T cell activation [ 71 ].…”

“…GVAX Pancreas combined with CRS-207 prolonged the survival of patients with metastatic pancreatic cancer in clinical trials [ 79 ]. GVAX has also been combined with other treatments, but the clinical efficacy did not meet expectations [ 70 , 76 , 80 ]. As tumor stromal cells also contribute to the progression and metastasis of tumors, they should be eliminated to achieve better therapeutic efficacy against tumors [ 81 ].…”