Cancer therapeutic vaccines can seem like the smartest but laziest kid 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 ClinicalTrials.gov 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 the 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 rituximab, 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 marshalling 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 the 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-Guérin) 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 sipuleucel-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.