San Francisco, CA—The use of immunotherapy for the treatment of gastrointestinal (GI) cancers should become a reality in the not-too-distant future. Uncovering the signaling networks within the tumor microenvironment that regulate host immune responses is leading to strategies to alter these responses to treat GI malignancies. Combinations of therapies that can induce T cells into a tumor and activate the T cell response will most likely be needed. Such combinations are already under investigation, said Elizabeth M. Jaffee, MD, Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, in her keynote address at the 2014 Gastrointestinal Cancers Symposium.
“The main goal of immunotherapy is to raise an army of T cells to attack the tumor. These T cells need to get into the tumor, but they also have to be activated,” said Dr Jaffee.
Achieving an anticancer response may require not only targeting a specific antigen, but also costimulation to present antigens in the right form so that an activated T cell can be generated. Activated T cells in combination with 1 or more immune checkpoint blockers will be necessary for a response.
Vaccines are especially needed for cancers, such as pancreatic cancer, that do not naturally induce intratumoral immune responses. Effector T-cell infiltration is not a natural response to pancreatic cancer, Dr Jaffee said, but there is evidence that the immune system can be provoked in patients with pancreatic cancer.
Combining gemcitabine (Gemzar) with an agonist signal (CD40 agonist) was able to reverse an immunosuppressive tumor microenvironment and induce tumor regression, which means that “T cells are likely getting in and are associated with the clinical response,” she pointed out.
A pancreatic tumor vaccine study at Johns Hopkins provides new evidence for antitumor immunity. The vaccine is administered 2 weeks before surgical resection of the tumor. A single dose of intravenous cyclophosphamide is given with the vaccine to enhance immune response.
Cyclophosphamide allows trafficking of antigen-specific T cells to the tumor. “In 85% of the patients studied, we found lymphoid aggregates coming into the tumors,” said Dr Jaffee. “They’re located throughout the tumor and they’re located around the tumor. When examined closely, they look like Germinal Centre-like structures; they stain for T cells on the outside, B cells on the inside.”
It is known that vaccines can induce tumor-infiltrating lymphocytes in traditionally “nonimmunogenic” tumors. “But vaccine-induced infiltrating T cells likely get downregulated by suppressive mechanisms within the tumor,” Dr Jaffee said. “Vaccines must be given with agents that modulate these suppressive mechanisms to activate the T-cell response.”
In mice, anti–PD-1 therapy enhances the infiltration of vaccine-induced tumor-specific infiltrating lymphocytes. In pancreatic cancer, regulatory pathways can be modulated to enhance vaccine efficacy. Ipilimumab (Yervoy) plus a vaccine extended median overall survival (OS) compared with ipilimumab alone in a small pilot study of patients with metastatic pancreatic cancer in whom 2 or more chemotherapies had failed.
Targeting more than 1 checkpoint pathway at a time appears to produce a synergistic response. Early data from patients with melanoma suggest that the combination of anti–PD-1 and ipilimumab produces more frequent and deeper responses, but with a significant increase in toxicity.
Several strategies to enhance response are being explored. Two vaccines may be better than 1, Dr Jaffee said. A vaccine platform based on live attenuated, double-deleted Listeria monocytogenes targeting mesothelin (GVAX/CRS-207 combination) improved median OS in patients with metastatic pancreatic cancer in whom chemotherapy was refused or failed. “Listeria is an intracellular bacterium that induces a T-cell response against antigen targeting the tumor, but it also induces T-cell responses against helper T cells that propagate that T-cell response,” said Dr Jaffee.
Combinations of immune checkpoint inhibitors given with vaccines is another possible strategy. Ipilimumab plus a GVAX vaccine or anti–PD-1 therapy plus a GVAX vaccine with a Listeria boost are potential options.
Combinations of immune-activating agents with methylation-targeting agents are another possibility, because hypomethylation uncovers inflammatory signals within the tumor microenvironment, Dr Jaffee said. Engineering T cells that target GI cancer tumor antigens is also being explored.