Daniel M. Keller, PhD

May 03, 2012

May 3, 2012 (Miami, Florida) — In a multicenter clinical trial of an autologous heat-shock protein-peptide vaccine, patients with recurrent glioblastoma multiforme (GBM) who received the vaccine survived longer than comparable historical control patients who received various other therapies.

Reporting results here at the American Association of Neurological Surgeons (AANS) 80th Annual Meeting, Andrew Parsa, MD, PhD, professor in residence and vice chairman of neurological surgery at the University of California at San Francisco (UCSF), noted that these early results show that the vaccine may be beneficial and that immunotherapy may be less toxic than currently used chemotherapy or antiangiogenic factors.

The vaccine, HSPPC-96, is produced individually for each patient using that patient's own resected tumor tissue. It uses glycoprotein-96 (gp-96) associated with cancer-specific antigenic peptides to induce antitumor antibodies. Heat-shock proteins are ubiquitous soluble components of nucleated cells and act as chaperones for all peptides in the cell, including mutated and tumor peptides.

The vaccine is produced by a commercial firm by extracting heat-shock proteins and their associated peptides. It is then tested for biological activity and sent back to the clinician within 48 hours of surgery. It is injected intradermally, engages local antigen-presenting cells (APCs), and activates the APCs, which travel within the bloodstream and ultimately activate and expand T cell populations in lymph nodes. The vaccine is given 4 times, 1 week apart, and then every 2 weeks until the vaccine runs out.

Current standard therapies are maximal surgical resection, radiation therapy, and temozolomide at initial diagnosis. Therapy of recurrence includes maximal resection, the implantation of chemotherapy-impregnated wafers, and possibly the use of antiangiogenic therapy. There are anatomic limitations to the use of wafers, and antiangiogenic factors can promote the emergence of a more aggressive phenotype tumor as well as inhibit wound healing and promote infection.

Multiple Evidence of Vaccine Efficacy

This phase 2 trial enrolled 43 patients with a median age of 53 years and a Karnofsky Performance Status score of at least 80.

Dr. Parsa and colleagues showed that after the series of immunizations, peripheral blood T cells released interferon-gamma when exposed to the vaccine but did not react to a control, recombinant gp-96. Similarly, the vaccine enhanced CD8+ T cell and natural killer (NK) cell responses. Interferon-gamma responses were also enhanced in tumor biopsy tissue after the immunization regimen.

Most importantly, patients benefited in terms of survival compared with similar surgical populations treated with various other therapies. The patients who received HSPPC-96 survived a median of 47.6 weeks, and 93% were alive at 6 months. "It compares quite favorably to a contemporary cohort control group as well as historical controls," Dr. Parsa said.

In the contemporary control database of UCSF patients not receiving the vaccine, patients had a median survival of 32.8 weeks, with 68% alive at 6 months. Historical control patients from other studies showed median survivals of 31.4 weeks and 39.8 weeks, with 6-month survivals of 56% and 62%, respectively.

Patients tolerated the vaccine well, and no treatment-related grade 3 or 4 toxicities were noted.

A randomized phase 2 trial powered to facilitate registration of the vaccine is beginning. The endpoint will be overall survival using the vaccine in combination with bevacizumab compared with bevacizumab alone.

Dr. John Sampson, MD, PhD, professor of surgery, immunology, pathology, and radiation oncology at Duke University Medical Center in Durham, North Carolina, critiqued the study and called it "very promising work," because conventional therapies are quite limited by nonspecific damage that they cause to normal tissue. So immunotherapy is an important and specific approach to brain tumor treatment.

He said challenges in the field are that brain tumor clinical trials are small, nonrandomized, occur at a single site, and are often based on drugs developed for other diseases. "I compliment Dr. Parsa and his group for really moving forward from their phase 2 single-arm trial now to a multicenter, randomized trial," Dr. Sampson said. "This is the only way that we'll understand whether some of these therapies actually have any efficacy."

He said a remaining question is whether vaccines need purified tumor antigens, which are difficult to isolate. "Dendritic cells pulsed with peptides or heat-shock proteins pulsed with peptides have the problem that they may also initiate immune responses to normal proteins," he cautioned.

Dr. Parsa disclosed that he has no financial relationship with the manufacturer of the vaccine. Disclosure information has been requested from Dr. Sampson but has not yet been received.

American Association of Neurological Surgeons (AANS) 80th Annual Scientific Meeting. Abstract #704. Presented April 17, 2012.


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