Cancer Vaccines: Asymptotically Approaching Product Approval - Cancer vaccines under development have proven safe and well-tolerated, but establishing efficacy remains a challenge. - BioPharm


Cancer Vaccines: Asymptotically Approaching Product Approval
Cancer vaccines under development have proven safe and well-tolerated, but establishing efficacy remains a challenge.

BioPharm International

  • Provenge, Dendreon's vaccine for treating prostate cancer. This vaccine is prepared with the patient's monocytes enriched by elutriation from leukapheresis blood cells. The monocytes are placed in cell culture without exogenous cytokines and loaded with the tumor antigen, which is a fusion protein of full-length PAP and GM-CSF. After 40 hours in culture, the antigen- loaded APCs are washed and formulated for infusion into the patient.13 In hormone-refractory prostate cancer patients treated with Provenge (N = 82) the median survival was 25.9 months compared to 21.4 months in the placebo (APCs without antigen) group (N = 45).14 Dendreon received an FDA approvable letter on May 8, 2007, with licensure pending Phase 3 clinical trial results to support the efficacy claim.15
  • Argos Therapeutics is testing a DC vaccine for the treatment of renal cell carcinoma.16 The vaccine is monocytes grown with GM-CSF and IL-4, transfected with autologous tumor RNA and matured with IL-1β, IL-6, TNF-α, and PGE2.17
  • UVIDEM is a DC vaccine for treating melanoma. It is prepared by culturing the patient's monocytes with IL-13 and loading them with lysates from allogeneic melanoma cell lines.18
  • ODC Therapy has licensed DC vaccine technology from the Baylor Research Institute for commercial development. The vaccines are prepared as either CD34+ cells with GM-CSF, TNF-α, Flt-3L and loaded with MART-1, gp-100, tyrosinase and MAGE-3 peptides,19 or monocytes with GM-CSF, IL-4, CD40L, TNF-α and loaded with killed allogeneic melanoma cells.20 Both vaccines elicited anti-tumor immune responses and prolonged survival in Stage IV melanoma patients.

Commercial Challenges for Cancer Vaccines

Figure 2. General production scheme for manufacture of dendritic-cell cancer vaccines
Although each of the cancer vaccines mentioned above has unique development and cGMP compliance challenges, they share some common manufacturing and quality control release issues. Figure 2 outlines a general scheme for the manufacture of DC vaccines. This scheme has two distinct paths. One path, which also applies to antigen-based vaccines, depicts the steps involved in manufacture of the TAAs. The other path depicts the steps to manufacture the TAA-loaded DC. Criteria for the manufacture and release of recombinant proteins and synthetic peptides are not discussed here, since they have been established for licensed biological products. It should be noted that regulatory agencies are still considering requirements for the manufacture and release of cell-based cancer vaccines.

Tumor Antigen Manufacture and Release

The first step in the TAA preparation process is establishing control over the growth and stability of the allogeneic human tumor cell lines or autologous patient tumor cells. Although numerous allogeneic human tumor cell lines exist, the potential drawbacks to their use as sources of TAAs include: 1) a potential lack of traceability to the original tumor isolate, 2) the possible exposure of the cells to animal products, e.g., serum, used in cell culture, and 3) the difficulty in establishing cGMP manufacturing control and quality compliance. Although cGMP-compliant master and working cell banks can be established for allogeneic tumor cell lines, this is less likely to occur when autologous tumor cells are the source of TAAs, thus presenting a different set of challenges, including: 1) whether enough tumor cells can be harvested from the patient, 2) whether the cells can be established and expanded in cell culture to the numbers needed to prepare the vaccine, 3) whether the cells express the desired TAAs in the amounts needed to prepare a vaccine to meet the vaccination schedule for the patient, and 4) how a cGMP process will be developed that accommodates the manufacture of a consistent vaccine from different, noncharacterized tumor explants.

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