New vaccines changing cancer treatment landscape

SAN DIEGO-The body’s immune system can be directed to shrink tumors and prevent new ones in a variety of tumor types, according to investigators who described new cellular strategies and vaccines at the 2008 American Association for Cancer Research annual meeting.

Hormone-Refractory Prostate Cancer

Ipilumimab (Medarex and Bristol-Myers Squibb), a fully human anti-CTLA-4 antibody, produced clinical benefit in metastatic hormone-refractory prostate cancer patients in two studies.

In a phase I trial of 24 patients by University of California, San Francisco, investigators, 3 of 6

patients receiving the highest dose had a greater than 50% decline in PSA level (abstract 2539).

Significant reductions in metastases were also observed on imaging, including a partial response in the liver, reported Lawrence Fong, MD, a hematology/oncology researcher at UCSF. “Ipilumimab works by removing the brakes on the immune system. We combined the anti-CTLA-4 antibody with a growth factor (GM-CSF), which enhances antigen presentation, to give a one-two punch. We think of it as educating the immune system,” he said.

Anti-tumor activity was also seen for ipilumimab combined with the GVAX vaccine (Cell Genesys) in a phase I dose-finding trial of 12 patients (abstract 2538). Patients received GVAX (one dose followed by bi-weekly doses for 24 weeks), with ipilumimab given every 4 weeks.

Five of 6 patients responded, and PSA declines greater than 50% were maintained for up to 16 months. Among those with a PSA decline, two had complete resolution of multiple lesions on bone scans, one had resolution of metastases in the abdominal lymph nodes, and one had improvement in bone pain, reported Saskia J.A.M. Santegoets, PhD, of the Vrije Universiteit Medical Center, Amsterdam.

Listeria vaccine for cervical cancer

Lovaxin C (Advaxis), a live Listeria cancer vaccine, produced stable disease in seven patients and a partial response in one patient in a phase I/II study of 13 patients with heavily pretreated metastatic cervical cancer.

The responder (stage IVb) remains tumor-free and has normal blood markers, said John Rothman, PhD, vice president of clinical development at Advaxis (abstract 225).

“We bioengineer Listeria to attenuate it and cause it to secrete a tumor-specific antigen [HPV-16-E7] fused to a listerial protein. By doing this, we focus a strong immune attack against the antigen in question,” Dr. Rothman commented. “This construct targets HPV-related cancers, so there are more targets than cervical cancer [head and neck, anal, genital].”

ADEPT approach

Antibody-directed enzyme prodrug therapy (ADEPT) uses a two-step approach: An antibody transports an enzyme directly to the tumor and a prodrug initiates the anti-tumor attack when it comes into contact with the enzyme. ADEPT showed efficacy in a phase I trial of 43 patients with solid tumors (abstract LB-200). Anti-enzyme antibodies developed in 100% of patients: 44% responded and 69% derived clinical benefit, said Richard Begent, MD, of University College London.