"The main lesson learned in the prostate cancer trials is that the stage of cancer is critical to the success of a cancer vaccine," said BioSante president and chief executive officer Stephen Simes in an e-mail interview. "Those men who had a predicted survival (Halabi score) of 18 months or more received a benefit from the cancer vaccine, but those with a predicted survival [of less than] 18 months did not. Overall, the mean predicted survival of the men in the prostate studies was 13-16 months, hence the less-than-positive outcome. ... The men in the Provenge trials had a predicted survival of 21 months before therapy, and hence the better outcomes."
The company is finalizing a regulatory submission to remove a clinical hold on the prostate cancer vaccine, and it plans to start an open-label, phase II trial of a neoadjuvant vaccine combined with an immune checkpoint regulatory molecule. The trial will enroll patients who have a lower disease burden than do those in the previous prostate cancer vaccine trials, according to Mr. Simes.
The failed European antimelanoma vaccine trial tested the hypothesis that raising antibodies to a cell-surface component (ganglioside) could result in an antitumor effect, but "we have no good data in melanoma that antibodies against surface markers are good for very much. That’s not the mechanism the host response uses to kill tumors when it is successful," Dr. Gajewski said.
Therapeutic vaccine developers are also challenged by the considerable defenses thrown up by tumors themselves, noted Dr. Mario Sznol, vice-chief of medical oncology and codirector of the melanoma program at Yale Cancer Center in New Haven, Conn.
"None of us would expect that vaccines in general would have a very strong effect, because we already know that there are a lot of regulatory checkpoints in T-cell activation that occur beyond the initial immunization, and we know that there are a lot of things that go on in the tumor microenvironment that prevent those T cells from working well there. So while a vaccine might have some activity and be a necessary or adjunctive component to another kind of immune therapy, vaccines by themselves probably would have limited effect," he said.
Dr. Sznol, who investigates methods for overcoming tumor resistance to immune mechanisms, said that vaccines are instead likely to play an adjunctive role in combination with other, more potent immunotherapies, such as ipilimumab or cytokines such as interleukin-2.
"Vaccines might direct the immune system better or contribute to the effect, but looking at it the other way – as the vaccine being the principal component of that immunotherapy – is, I think, the wrong way to look at it," he concluded.
New Platforms, Targets, Challenges
Dr. Gajewski said that the vaccines most likely to succeed are those developed through a stepwise scientific approach, which involves methodical selection of antigens in combination with the adjuvants that produce the optimal cytotoxic T-cell response.
Therapeutic vaccines currently in development use antigens that are derived from proteins, carbohydrates, glycoproteins, glycopeptides, or gangliosides, as well as attenuated tumor-associated antigens that are employed in autologous or allogeneic formulations.
Other strategies include DNA or RNA sequences that code for cancer-associated antigens either delivered singly (naked nucleic acid vaccines) or transfected into viral vectors. Some research teams are focusing on the development of vaccines that are targeted against antigens in specific tumor types, whereas others aim for targets that are common to several different cancer histologies. The latter antigens include MAGE-3 (melanoma-encoding antigen); NY-ESO-1, found in both melanoma and synovial cell sarcoma; and WT-1, the Wilms tumor antigen that is widely expressed in leukemia.
But getting the best cytotoxic T-cell response and incorporating it into off-the-shelf vaccines are only half the battle, Dr. Gajewski said.
"The other half of the equation is whether the tumor and the tumor microenvironment are susceptible to killing by immune cells. Tumor resistance – to the activated immune cells, to cytotoxic T cells, to the effector phase of antitumor immune response – is dominant in many cases" he noted.
Many vaccine researchers are working to develop end runs around the tumor inhibitory pathways that either inactivate T cells when they infiltrate or keep them out of the tumor altogether.
"We have been able to catalog patterns of gene-expression profiling in tumors that correlate positively or negatively with outcomes, and that has identified a set of [biological] processes that seem to represent the barriers [to immunity] at the level of tumor site. And now [that we understand] those, it’s enabling ways to intervene and change the susceptibility of the tumor site to the immune response that’s induced," Dr. Gajewski said.