Robert Petit, PhD
Earlier this week, Advaxis and Merck announced a clinical trial collaboration agreement to evaluate the combination of the PD-1 inhibitor pembrolizumab (MK-3475) and the Listeria monocytogenes-LLO cancer immunotherapy ADXS-PSA. The phase I portion of the trial will aim to establish an appropriate dose regimen for ADXS-PSA alone and in combination with pembrolizumab. The phase II portion will evaluate the safety and efficacy of the combination. The study is planned to begin in early 2015.
To gain further insight into the ADXS-PSA immunotherapy and the rationale behind the combination study, OncLive
interviewed Robert Petit, PhD, the chief scientific officer at Advaxis, about the collaboration and future strategies.
OncLive: Why is this drug being looked at in combination with pembrolizumab in prostate cancer?
That’s actually a very interesting question. Most malignant cells that succeed in developing into cancers do so because they avoid the parts of the immune system that are responsible for protecting us against cancers. The human body has mechanisms of immune tolerance that it uses to protect normal tissues from misdirected attacks by the immune system. Cancers, oftentimes, escape the immune system because they can hide behind the same protections used by normal tissues.
There are several different mechanisms of immune tolerance used within our bodies and certain cancers may be protected by more than one. One of those mechanisms involves something that’s called PD-1. Activated immune cancer fighting cells express a receptor for PD-1 and when PD-1 binds to its target, it shuts off the cancer-fighting cell. When the T cells that are coming into the neighborhood of a tumor to fight against it, the tumor has the ability to bind to PD-1 by expressing its ligand, then the T cell gets shut off before it ever enters the tumors. Pembrolizumab blocks the PD-1 receptor and keeps the T-cells active and on the job.
Another mechanism of immune tolerance involves cells that live inside tumors and send out clouds of biologic chemicals that also can shut down activated T cells in the area.Â Scientists know these as Tregs and MDSC cells. Even if the T cells get past the PD-1 they can still be shut down by Tregs and MDSCs in the tumors. ADXS-PSA has the ability to decrease the number and activity of Tregs and MDSCs inside the tumors in tumor models.
The point behind this combination is that ADXS-PSA stimulates the immune system to generate a new crop of cancer-fighting T-cells that recognize a key target on the tumor cells, PSA. Then the pembrolizumab PD-1 blockade masks PD-1, which the tumor may be hiding behind, and amplifies the number of cancer fighting cells that are produced. Once these cancer-fighting cells get inside the tumor tissue itself, past the PD-1 blockade, they find that the ADXS-PSA had disabled the Tregs and MDSCs inside the tumor, allowing the cancer-fighting cells to do their job and eliminate cancer cells. Therefore, the combination treatment provides a fresh crop of cancer-fighting cells, while at the same time, overcoming two different mechanisms of immune tolerance that could be protecting the prostate cancer inside patients.