Immunotherapy: Enlisting The Immune System To Fight Cancer

Researchers are directing the body's immune system to shrink tumors and prevent new ones from forming. Data presented at the 2008 Annual Meeting of the American Association for Cancer Research, April 12-16, detail how cellular strategies and new vaccines are changing the cancer treatment landscape.
The first use of a live listeria cancer vaccine in man

Phase I/II trial results have shown that the live Listeria cancer vaccine, Lovaxin C, is safe for humans. In addition, three women in the cervical cancer trial had approximately 20 percent tumor reductions, researchers report.

"We are using Listeria to deliver tumor-specific antigens to the immune system in a manner that results in maximal immune and tumor-clearing response," said John Rothman, Ph.D., vice president of clinical development at Advaxis, which is developing Lovaxin C.

The trial included 15 women with progressive, recurrent or advanced cervical cancer. All patients had failed chemotherapy, radiotherapy or surgery. The women had metastatic disease and most were stage IVb.

Listeria monocytogenes infects antigen presenting cells (APCs) -- "a very special piece of immune real estate," Rothman said. These cells consume foreign invaders and instruct the immune system to attack them. Listeria thrives within APCs and thus directs an immune response.

"We bioengineer Listeria both to attenuate it and to cause it to secrete a tumor-specific antigen fused to a listerial protein, which makes it more effective than Listeria that just secretes the tumor antigen," Rothman said. "By doing this we focus a very strong immune attack against the antigen in question, which is typically specific to a tumor."

"What we're doing is taking a lot of evolution that enabled Listeria to infect human immune systems, and an equal amount of evolution that enables humans to get rid of Listeria once this occurs. We are then co-opting and redirecting all of these complex immune responses and targeting them against cancer," Rothman said.

The researchers divided the patients into three groups of five; each group received two doses of either 1x109, 3.3x109 or 1x1010 units of Listeria at three-week intervals. They administered ampicillin five days after each dose, first intravenously and then orally for 10 days.

Each patient developed flu-like symptoms, including fever, chills and nausea with or without vomiting. In the lower doses, these symptoms were treated with non-prescription non-steroidal anti-inflammatory drugs (NSAIDs) and anti-emetics. Patients in the highest dose group had the same but more severe symptoms.

Rothman used the RECIST criteria to assess the tumors in 13 patients. At the end of the study, five patients had progression of their cancer, seven were stable, and one patient showed a partial response to the therapy. Three of the seven stable patients had tumor reductions of about 20 percent.

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

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

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.

"Higher doses of ipilimumab combined with the GVAX vaccine is showing a lot of success in increasing anti-tumor activity in these patients," said Saskia J.A.M. Santegoets, Ph.D., a researcher in the Department of Pathology and Division of Immunotherapy at the Vrije Universiteit Medical Center in the Netherlands. "We're encouraged by the results of this phase I trial and expect ongoing analyses to yield more valuable data about the GVAX/ ipilimumab combination."

In this trial, the vaccine was administered with escalating doses of anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab. Researchers believe that the combination of these two immunotherapies increases one's immunity to prostate cancer.

Twelve patients were enrolled in this study. All were given the same doses of GVAX (a 500 million cell first dose followed by bi-weekly 300 million-cell doses for 24 weeks), and, in groups of three, different quantities of ipilimumab administered every four weeks (.3mg, 1mg, 3mg, or 5 mg).

Anti-tumor activity was seen in five of the six patients who received the two highest doses of ipilimumab, including PSA-level declines of greater than 50 percent; these PSA declines were maintained in four of these patients for at least six months, and up to 16 months. Among the patients with PSA-level declines, researchers noted complete resolution of multiple lesions on bone scans in two patients, resolution of cancer spread to abdominal lymph nodes in one patient, and improvement in bone pain in one patient.

The ongoing phase I trial of this combination has enrolled an additional 16 patients with hormone-resistant prostate cancer into an expansion cohort.

Evidence of Efficacy of Antibody Directed Enzyme Prodrug Therapy (ADEPT) in a Phase I Trial in Patients with Advanced Carcinoma

A two-step drug therapy that selectively targets tumors may hold promise for some patients with advanced cancers, according to results of a clinical trial directed by researchers in London.

Scientists at the University College London's Cancer Institute and the Royal Free Hospital used a technique called antibody-directed enzyme prodrug therapy (ADEPT) in 43 patients with previously treated, advanced colorectal, gastro-esophageal, breast, gallbladder, peritoneal, appendix, or pancreatic cancers, or cancers of unknown primary site. The patients received one, two or three ADEPT treatments over a period of two to 10 days, at dosages ranging from 37 mg/m2 to 3,226 mg/m2.

"We found clinically significant responses in 44 percent of patients," said senior author Richard H. Begent, M.D., professor of oncology at the University College London's Cancer Institute. "These results support the case for conducting a randomized phase II clinical trial."

ADEPT is a two-step treatment for cancer that uses an antibody to carry an enzyme directly to the cancer cells. First, an antibody is given with an enzyme attached. Next, a prodrug (inactive anti-cancer drug) is administered. When the prodrug comes in contact with the enzyme, the resulting chemical reaction activates the anti-cancer drug, which is then able to destroy cancer cells while sparing nearby healthy tissue.

In this trial, the researchers gave patients an intravenous dose of MFECP1, a recombinant fusion protein consisting of a fragment of an antibody raised against the substance carcinoembryonic antigen (CEA), which is produced by the cancer, and carboxypeptidase

G2 (CPG2), an enzyme that activates a prodrug. Then, researchers gave patients an intravenous bis-iodo phenol mustard prodrug which is activated by the enzyme within the cancer.

Anti-enzyme antibody developed in 40 percent of patients having a single treatment, 75 percent of patients after two treatments and 100 percent of patients after three treatments.

In addition, imaging scans showed that four of nine patients had partial response, meaning their tumors shrank, at a total prodrug dosage of at least 900 mg/m2. This response was confirmed by a 25 percent reduction in blood levels of CA 19-9, a tumor marker, in three patients who had raised levels before treatment. Stable disease, as defined by RECIST criteria, was seen in 69 percent of patients who had a total prodrug dose of at least 900 mg/m2.

The most common side effects were thrombocytopenia (low platelet count) and neutropenia (low white blood cell count). Side effects were deemed tolerable.