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Despite setbacks, Ca vaccine trials continue: a search on shows more than 100 studies that are recruiting or in active planning.

Cancer therapeutic vaccines can seem like the smartest but laziest kids in the class: always showing promise, but largely failing to live up to their potential.

Despite several flameouts in recent years - notably, a failed trial for a nonspecific therapeutic vaccine for prostate cancer using the GVAX platform, and the tanking of two different approaches to vaccinating patients against malignant melanoma - the pace of vaccine research seems to have quickened.

A search for "cancer therapeutic vaccine" on shows more than 100 studies that are either recruiting or in active planning. BioSante Pharmaceuticals alone has 15 phase I and phase II clinical studies involving vaccines based on the GVAX platform against acute and chronic myeloid leukemias, breast cancer, pancreatic cancer, and other tumors.

Is this, as Samuel Johnson said of second marriages, the triumph of hope over experience? Not so, say leading vaccine researchers. Indeed, vaccine development is flourishing, in large measure because of the lessons learned from earlier defeats, and it got a shot in the arm with the approval last year of sipuleucel-T (Provenge) as the first cancer therapeutic vaccine.

"Basic immunology - such as the relationship between a growing cancer and the host immune response - is becoming better understood. We also understand better how to vaccinate. There were some vaccines that went forward because they were doable, and not necessarily because they were ideal or optimized," said Dr. Thomas F. Gajewski, president of the International Society for Biological Therapy of Cancer.

Helping Immune System Help Itself

The concept of therapeutic vaccines is tantalizing: Give the patient the right antigen, delivered with a suitable adjuvant, and you can train the immune system to recognize malignant cells as foreign.

In contrast, other types of immunotherapeutic agents - such as rituximab (Rituxan), trastuzumab (Herceptin), and ipilimumab (Yervoy) - are monoclonal antibodies that are directed against specific cellular targets: the CD20 receptor on B cells in the case of ritux-imab, the HER2 protein in cancer cells for trastuzumab, and the CTLA-4 surface antigen on T cells for ipilimumab.

Ipilimumab, which is delivered with a peptide vaccine to enhance immune response, was the first agent to demonstrate a survival advantage in phase III, randomized trials for patients with malignant melanoma (with peptide vaccine alone as the comparator), and it could receive Food and Drug Administration approval this month.

But not all cancers share the same targets, and marshaling the body's defenses against melanoma in particular is a good bit trickier than getting it to raise antibodies against polio or smallpox, investigators say. A history of setbacks proves it.

For example, at the 2007 annual meeting of the American Society of Clinical Oncology, investigators in MMAIT (Malignant Melanoma Active Immunotherapy Trial) reported that patients with resected metastatic, stage III or stage IV melanoma gained no overall benefit from a combination of BCG (bacille Calmette-Guerin) and allogeneic melanoma vaccine (Canvaxin).

Similarly, at ASCO 2008, investigators in the phase III EORTC (European Organisation for Research and Treatment of Cancer) 18961 trial reported that an adjuvant vaccine that was targeted against a ganglioside that was overexpressed on most melanoma cells did not improve distant metastasis-free survival, and that an early interim analysis suggested a detriment to overall survival. (Subsequent analyses have suggested that earlier fears of harm from the vaccine may have been unwarranted, however.)

Antibodies Not Up to the Task

The goal of current therapeutic vaccines is to generate a cytotoxic T-cell response, primarily with CD8-positive effector T cells, something that has not been achieved with conventional vaccines that are primarily designed to induce antibodies.

"In most solid tumors, those antibodies are not going to be enough; they probably won't hurt, but they're not sufficient, and you need the T-cell response to get real tumor-cell killing," said Dr. Gajewski, a professor of pathology and medicine in the section of hematology/oncology at the University of Chicago.

GVAX in its earlier incarnation fell short of the mark because - unlike sip-uleucel-T, which is an autologous vaccine comprising transduced prostatic acid phosphotase cells unique to each patient - GVAX was not specific to the tumor characteristics of individual patients, Dr. Gajewski noted.

"GVAX was an allogeneic vaccine transduced to express granulocyte-macrophage colony-stimulating factor [GM-CSF], and that way you only have to express the molecule in one cell line, and then you try to administer it to all the patients hoping that there's enough in common that they induce the immune response that recognizes the tumor in that patient. That's true in some cases; in other cases, it's not," he added.

"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.

Dr. Gajewski has received research support for clinical trial participation from Bristol-Myers Squibb, Glaxo-SmithKline-Bio, Incyte, Novartis, Eisai, and Genentech/Roche. He has served on advisory boards or served as a paid adviser to Bristol-Myers Squibb, Glaxo-SmithKline-Bio, Incyte, Eisai, and Genentech/Roche. Dr. Sznol has received honoraria or served as a consultant to Bristol-Myers Squibb, Genzyme, and Pfizer.
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Title Annotation:ONCOLOGY
Author:Osterweil, Neil
Publication:Internal Medicine News
Date:Mar 15, 2011
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