Clinical Research: Phase 1 - Phase 4

Why Have Cancer Treatment Vaccines Fallen Short?

Vaccines were once thought to have great potential for combating some types of cancer, but reality has failed to match those expectations. To date, vaccines have failed to play a major role in the pursuit of immune response for oncology patients.

There have been two notable successes — sipuleucel-T (marketed as Provenge) is approved to treat prostate cancer and T-VEC (sold under the trade name Imlygic) to treat melanoma — but many other vaccines that showed good promise in Phase II studies have failed to improve survival in Phase III trials. For example:

  • Whole-cell vaccines aimed at allergenic melanoma cells and cell lysates
  • Directed tumor antigens such as the MAGEA3 (for melanoma treatment) and the multifaceted oncoprotein MUC1
  • Manipulated oncolytic viruses such as T-VEC

Consider the proposed use of T-VEC in patients with metastatic colorectal cancer. Clinical trial results showed little evidence of tumor shrinkage or delay in disease progression, but the FDA nonetheless found the resulting 4.1-month improvement in patients’ median survival significant for those who have few or no other therapeutic options.

A recurring issue we’ve observed is that vaccines initially induce immune response to the vaccine itself and not against the tumor, as the immune system mainly recognizes neoantigens from “passenger” mutations rather than shared antigens.

There should be different antigens for each tumor, given that most immune-responsive tumors “autovaccinate,” but immune regulation prevents an effective response.

Some other things we’ve observed:

  • A vaccine must incorporate autologous tumor cells
  • Even if a vaccine enhances antitumor immunity, cells are likely to be suppressed in the tumor microenvironment

Absent future breakthroughs in immune checkpoint control, it appears unlikely that vaccines will play a major role in the pursuit of immune response.