Advaxis Scientific Officer Illuminates ADXS-PSA/Pembrolizumab Collaborative Study

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.

OncLive: Why is this drug being looked at in combination with pembrolizumab in prostate cancer?

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.Petit: 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.  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.

How many patients do you hope to enroll in this trial?

Could ADXS-PSA have utility in other settings of prostate cancer?

If this trial is successful, what are the next steps, both for the combination of drugs and the relationship between the companies?

Together, they work very well in laboratory models.  They both help each other and team up in the fight against the cancer. We are hoping that we will soon see the same teamwork between these treatments in patients with prostate cancer. The size of the study is a little bit variable, because we’re working through dose escalations. The idea is to get in the neighborhood of 40-50 patients that are successfully treated with the combination, so we can get an idea of how well the two drugs work together in fighting cancer and controlling the advance of prostate cancer. With good data, we can move forward in the clinical development of the combination.ADXS-PSA is specific for prostate tissue.  The initial studies will focus on prostate cancer.  It’s not too far of a reach to think there might be a role sometime in the future where there could be investigations in pre-malignant diseases like prostate hypertrophy but for now there are about 240,000 new cases of prostate cancer each year in the U.S. that need our attention. This current investigation is in patients who have already been treated at least once for hormone-resistant prostate cancer and need a more effective option. We hope that, eventually, if the combination shows to be effective, we can move toward earlier stages of the disease and offer an immunologic way to eliminate the tumors.There’s a lot of interest in prostate cancer and hope for an effective immunotherapy that will eliminate prostate cancer. The two companies involved in this combination actively will look at the results of this clinical trial and discuss the appropriate next steps in clinical development together.  We’re proud to be working with an excellent company like Merck and both companies are excited about the potential for the combination treatment.