Using vaccines to prevent cancer in general is now becoming feasible. Cancer vaccines in use or in development at this time are of 2 general types: those derived from a single tumor and are designed to elicit immunity to that particular tumor in that particular individual host; and those designed to provoke an immune response to that particular type of tumor in any host. The latter type can be mass produced, whereas vaccines of the first type are restricted to the host of origin.
Autologous Vaccines
At the time of biopsy or surgical excision, tumors are mechanically and enzymatically dissociated into single cells, then grown in tissue culture. When they are cultured in suspension with agitation, the cancer stem cells (CSCs) form spheroids, and other cell types do not. The CSCs are the progenitor cells of the specific tumor, much like bone marrow stem cells are the progenitors of the myeloid, erythroid, and megakaryocyte (platelet) cell lineages of human blood. After the CSCs are expanded, the spheroids are harvested, and their RNA is extracted. The messenger RNAs, which specify the proteins made by the CSCs, are converted to complementary DNAs, which are then amplified using the polymerase chain reaction. 8
Meanwhile, the patient’s peripheral blood mononuclear cells (PBMCs) are harvested from the blood by leukapheresis. The PBMCs are then enriched for monocytes by immunologic depletion of B and T cells. The monocytes are cultured in the presence of interleukin-4 and granulocytemacrophage-colony-stimulating factor (GM-CSF), and they become immature dendritic cells after 5 days. These immature dendritic cells are transfected with the amplified DNA from the CSC tumor spheres and grown for 2 more days in a medium supplemented with interleukin-1b (IL-1b), interleukin-6 (IL-6), tumor necrosis factor-α, and prostaglandin E2, then tested for markers characteristic of dendritic cells and frozen.
Aliquots of these transfected dendritic cells are injected into the patient at intervals over several months. Dendritic cells, which are the most efficient cells at eliciting an immune response, present the tumor CSC antigens to the patient’s immune system, which develops antibodies to the antigens presented on the dendritic cells and proceeds to destroy the tumor CSCs remaining in the patient’s tumor. Without its CSCs, the tumor is unable to revitalize itself, the rest of the tumor cells eventually die, and the tumor shrinks. The patient is monitored for immune response, and the tumor is regularly imaged. This vaccine is an example of therapeutic use: It can cause tumor regression. 8
Sipuleucil-T is another example of an autologous vaccine used for therapeutic purposes. The patient’s antigenpresenting cells (APCs) are harvested by leukopheresis. They are then cultured in the presence of the protein made by fusing prostatic antigen phosphatase (PAP) with the GM-CSF to form the fusion protein PAP-GM-CSF. These modified APCs are then reinjected into the same host. Sipuleucil-T is now FDA approved for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) and has been shown to extend life by approximately 4 months. 9
Universal Vaccine for a Specific Tumor
Cancer vaccines can also be prepared in a more conventional manner, analogous to the more commonly used vaccines, and given to all patients with that specific tumor. PROSTVAC is another vaccine for mCRPC as well as for earlier-stage prostate cancer. The DNA specifying prostate-specific antigen (PSA), the secreted protein expressed by the tumor, is mutated very slightly and inserted into a vaccinia virus (Figure). Also inserted into the vaccinia virus are DNAs encoding 3 proteins that
stimulate the patient’s immune system: B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte functionassociated antigen-3 (LFA-3).
