Immunotherapy: enlisting the immune system to fight cancer

The partial response patient — who was stage IVb at trial initiation — was given six chemotherapy courses and a radical hysterectomy. Currently, she is tumor- free and her blood tests are normal. Six of the 13 patients are surviving, with a median survival of 424 days. Median survival for all 15 treated patients is 327 days.

CTLA-4 blockade for hormone refractory prostate cancer: dose-dependent induction of CD8+ T cell activation and clinical responses: Abstract 2539

Blocking CTLA-4, a cellular molecule on lymphocytes that inhibits immune response, produced meaningful clinical benefits in patients with prostate cancer that hadn’t responded to hormone therapy, according to researchers.

“CTLA-4 blockade works by removing the brakes on the immune system. Our results show that enhancing immune responses in prostate cancer patients can lead to clinical responses,” said Lawrence Fong, M.D., a hematology/oncology researcher at University of California, San Francisco.

In a phase 1 trial in 24 patients with metastatic prostate cancer that was unresponsive to hormone therapy, Fong and colleagues treated groups of three to six patients with increasing intravenous doses of ipilimumab (0.5, 1.5 or 3 mg/kg), a fully human anti-CTLA-4 antibody, on the first day of each 28-day treatment cycle. There were four cycles in the trial. The researchers also gave the patients 250 mg/m2/d of granulocyte-macrophage colony-stimulating factor every day for the first two weeks of each cycle.

Researchers monitored T cell activation and toxicity. They performed prostate-specific antigen (PSA) and radiographic tests at enrollment and throughout treatment to assess clinical response.

Three of the six patients treated with the highest ipilimumab dose (3.0 mg/kg x 4) had confirmed declines in PSA levels of more than 50 percent. One of these patients had a partial response in cancer that had spread to the liver.

The researchers found that activation of lymphocytes occurred primarily in the higher doses. They also could detect lymphocytes targeting proteins expressed by prostate cancer cells in some patients following treatment.

Immune-related side effects -- including skin rash, diarrhea and a deficiency in pituitary hormone production -- were most common in the group receiving the higher ipilimumab doses.

Fong and colleagues will continue to study CTLA-4 blockade. “We are studying higher doses of anti-CTLA-4 antibody and look forward to beginning a larger phase 2 trial in the next three to six months,” Fong said.

Dendritic and T cell functions in patients with metastatic hormone-refractory prostate cancer treated with GVAX immunotherapy for prostate cancer and ipilumumab: Abstract 2538

Researchers have found a promising synergy of two therapies to treat metastatic prostate cancer that is resistant to hormone therapy. In a phase I trial, they observed that a combination of GVAX immunotherapy with ipilimumab lowered prostate-specific antigen (PSA) levels in some patients.