Using the Cancer Immunity Cycle to Improve Checkpoint Blockade Responses

In order to improve the efficacy of checkpoint blockade treatments in patients with breast cancer, it is necessary to consider treatment through the lens of the cancer immunity cycle.

In order to improve the efficacy of checkpoint blockade treatments in patients with breast cancer, it is necessary to consider treatment through the lens of the cancer immunity cycle, Elizabeth Mittendorf, MD, PhD, said at a session during the 2019 San Antonio Breast Cancer Symposium, titled “Immunotherapy in Breast Cancer: Enhancing Response to Checkpoint Blockade.”

The combination therapy of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) has been extremely influential in the treatment of unresectable locally advanced or metastatic PD-L1-positive triple-negative breast cancer, Mittendorf said.

According to Mittendorf, it is estimated that there will be approximately 268,000 new invasive breast cancer diagnoses in the United States annually. Of those, approximately 15% are triple-negative, about half of whom will have metastatic recurrence. Approximately 41% are PD-L1-positive, meaning that about 8755 patients each year may benefit from the combination therapy.

In order to improve treatments for other patients, however, such as those with PD-L1-negative disease, earlier stages of breast cancer, or other breast cancer subtypes, researchers must consider the cancer immunity cycle.

According to Mittendorf, the immunity cycle involves the release of cancer antigens, which are then presented for priming and activation of T cells. The T cells are then trafficked to the tumors, where they infiltrate and recognize cancer cells. Finally, the T cells kill cancer cells, and the cycle starts again. PD-L1 comes into play at the seventh step, Mittendorf said, in which it inhibits the killing of cancer cells.

“It’s largely thought that if tumors express PD-L1, the first 6 steps of the cancer immunity cycle are intact,” Mittendorf said. “One might then suggest that it’s defects in steps 1 through 6 of that cancer immunity cycle that contribute to a lack of response to PD-L1 therapy.”

There are several possible defects, Mittendorf said, each of which have their own outcomes. If there is a defect in the release and presentation of antigens, then there is no T cell response and the patient has an immunologically “cold” tumor. An excluded infiltrate occurs if the cycle develops T cells but they cannot traffic to or infiltrate the tumor. Finally, if the T cells infiltrate the tumor but are unable to kill the cancer cells, the patient has a non-functional immune response.

Understanding these various responses is vital to selecting the correct strategy to augment the response to checkpoint blockades, Mittendorf said.

In order to further explore therapeutic efficacy of immuno-biology in patients with breast cancer, Mittendorf and colleagues have established the Translational Resource for Immuno-Biology to Understand Therapeutic Efficacy (TRIBUTE), a multi-site effort to establish a repository of clinical data, biospecimens, and imaging results from patients with breast cancer treated with immuno-therapeutic agents.

“I think a real strength of TRIBUTE is that we’ll be obtaining on-treatment biopsies as well as biopsies at progression, and this is an effort that’s just being started with Dana-Farber being the first site to start enrolling,” Mittendorf said.

REFERENCE

Mittendorf, E. Immunotherapy in Breast Cancer: Enhancing Response to Checkpoint Blockade. Presented at: 2019 San Antonio Breast Cancer Symposium; San Antonio, TX: December 12, 2019.