Immunotherapy Holds Promise to Extend Survival in GI Cancers

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Recent advances in molecular technologies have enabled the dissection of inhibitory pathways within tumors and identification of inflammatory signals within the tumor microenvironment that regulate host immune responses. These responses can be altered to effectively treat cancers, including gastrointestinal (GI) malignancies, said Elizabeth M. Jaffee, MD, in her keynote address at the 2014 Gastrointestinal Cancers Symposium.

She provided an overview of immunotherapy for the treatment of GI cancers and described the signaling networks that regulate immune responses to different cancers.

“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 Jaffee, professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. “To do this…we have to understand the many signals within the tumor microenvironment that inhibit effective T-cell trafficking and function into tumors.”
A T cell has inhibitory and activating signals. Whether it receives a downregulatory or an activating signal is determined by the summation of signals that are ongoing in the tumor microenvironment, she said.

New immune checkpoint agents act on T cells. “This is important because if you don’t have a T cell in a cancer, the agent won’t work,” said Jaffee. Only 20% to 30% of renal cell carcinomas and 10% to 20% of colorectal tumors have T cells. For most cancers, therefore, immune modulation alone is insufficient for treatment; a T-cell–generating agent is also needed.

“Combinations are needed to achieve the full potential of the immune system to recognize and kill all cancers,” she said. “Understanding all of the signaling networks that regulate responses to the different cancers is necessary to figure out the right combinations.”

Many signals can inhibit an immune response in the tumor, and there are also many ways to activate T cells. The goal is to achieve an anticancer response when the tumor microenvironment naturally wants a procarcinogenic response, she explained. It 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.

Vaccines are especially needed for cancers that do not naturally induce intratumoral immune responses. Radiation and chemotherapies can act like adjuvants and potentiate the T-cell response obtained with vaccines.

Effector T-cell infiltration is not a natural response to pancreatic cancer, but there is evidence that the immune system can be provoked in pancreatic cancer, she said. The combination of gemcitabine and an agonist signal (CD40 agonist) was able to induce tumor regression, which means that “T cells are likely getting in and are associated with the clinical response,” she said.

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 IV cyclophosphamide is given with the vaccine in an effort 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 Jaffee. “They’re located throughout the tumor, and they’re located around the tumor. When examined closely, they look like germinal center–like structures; they stain for T cells on the outside, B cells on the inside.”

What is known so far is 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,” she said. “Vaccines must be given with agents that modulate these suppressive mechanisms to activate the T-cell response.”

In the mouse model, anti–PD-1 therapy enhances infiltration of vaccine-induced tumor-specific infiltrating lymphocytes. In pancreatic cancer, regulatory pathways can be modulated to enhance vaccine efficacy. Ipilimumab plus a vaccine extended median overall survival compared with ipilimumab alone in a small pilot study of patients with metastatic pancreatic cancer in whom 2 or more chemotherapies had failed.

Two vaccines may be better than 1, she said. A vaccine platform based on live attenuated, double-deleted Listeria monocytogenes targeting mesothelin (GVAX/CRS-207 combination) improved median overall survival in patients with metastatic pancreatic cancer in whom chemotherapy was refused or had 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.

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