Complex Chemoimmunotherapy Regimens on Horizon

NEW YORK--Advances in immunotherapy are opening a wide array of potential uses in combination with chemotherapy in advanced cancers. Speaking at the Chemotherapy Foundation XV Symposium, Ezra M. Greenspan, MD, referred to the "mind-boggling" number of variables--optimum timing, dosing, and route of administration, for example--involved in putting together experimental combination regimens.

Dr. Greenspan, clinical professor of medicine (oncology), Mount Sinai School of Medicine, New York City, and medical director of The Chemotherapy Foundation, acknowledged that it is relatively easy for the oncologist to look favorably on immunotherapy in patients with notoriously resistant cancers such as melanoma and renal cancer.

The dilemma may lie in devising regimens for their use in more common cancers for which a number of different chemotherapy agents are already available, such as lymphomas and breast, ovarian, and colon cancers.

He noted that immunotherapy received an important "boost" with the FDA approval of high-dose interferon-alfa (Intron A) as an adjuvant treatment to surgery in melanoma patients.

Even more provocative, he said, is the finding that GM-CSF alone influences the survival of patients with melanoma in the surgical adjuvant setting. "If the simple, solo use of interferon or GM-CSF can lead to positive survival effects in melanoma and lymphomas," he said, "then perhaps there may be a role for these agents in the more common breast, ovary, colon, and lung cancers."

Dr. Greenspan mentioned several immunotherapy agents under investigation that have the potential to be combined with chemotherapy. The ganglioside (GM 2) vaccine, extensively studied by a group at Memorial Sloan-Kettering, has yielded "encouraging results," he said.

Melanomas have been a target for immunotherapy with interleukin-2 (IL-2) in clinical research, he said, and IL-2 has also shown promise in renal cell cancer.

Rituximab, Monoclonal Antibody

 How and when to use the anti-CD20 monoclonal antibody IDEC-C2B8 (rituximab, Rituxan) in the treatment of low-grade lymphomas is now a major question, Dr. Greenspan said.

"This agent has an attractive toxicity profile and is equal to or better than CHOP in survival effects as first-line therapy in low-grade, favorable B-cell lymphomas," he said. "But, we need to study this monoclonal antibody against single chemotherapy agents for at least 1 to 2 years."

Whether this agent will be more effective against other lymphomas, such as mantle cell lymphoma or others deemed to be "incurable," also needs to be established, he added.

BCG as an interferon inducer has proved too weak to be useful as a solo agent, Dr. Greenspan said, but it is included as a booster in most vaccines, including the tumor-specific vaccine for colon cancer currently being studied in an ECOG trial. "The concept that multiple vaccine components are of major significance in immunological response to cancer is the most challenging development in the past year," he said.

Of particular interest, Dr. Greenspan noted, is the proposed prostate cancer vaccine, Oncovax-P, being investigated by Lynn Spitler, MD, of Jenner Biotherapies, San Francisco. It is made from recombinant prostate-specific antigen (PSA) formulated in liposomes with the solvent lipid A.

The safety of this vaccine was first demonstrated and stimulation of immunity confirmed in studies that showed a positive action on delayed cell-mediated immunity as well as a B-cell antibody response. BCG and GM-CSF were added to the vaccine, and then, to further increase the complexity of the treatment, cyclophosphamide in low doses was used to suppress certain leukocyte fractions. "This created a complex, combination chemoimmunotherapy," he said.