Advaxis Immunotherapies Complement PD-1 Antibodies

Hello, I’m Dr. Robert Petit, Chief Scientific Officer of Advaxis, and it’s my privilege to be a guest blogger and provide an update on my recent participation in the Bloomberg 2014 State of Healthcare Summit where I served as an expert on a panel titled, “The Future of Cancer Immunotherapy”. This panel brought immunotherapy to the forefront of healthcare discussions and drilled down into how current and future immunotherapies will play out in the clinical and commercial realms.

One topic addressed by the panel was the projection that 50% of cancer treatments will contain an immunotherapy within the next 10 years. I believe that Advaxis treatments could contribute significantly to this estimate. Chemotherapy and radiation have been staples of oncology for 40 years and we are all familiar with their successes and failures. Immunotherapy is coming of age and its growth in cancer treatment will be exponential as it promises the best balance between effectiveness and toxicity.

During the panel, I had the privilege to discuss that we are learning that cancer is really an individual disease within each patient. For each person, the mechanisms by which that particular cancer has been avoiding their immune system must be addressed if an immunotherapy is going to work. In other words, in order to fight immune tolerance, the immune system must “see the cancer differently in order to mount an effective defense against it. This is where Advaxis immunotherapies can really change the ability of the immune system to fight against cancer.

There are many mediators of immune tolerance in our immune systems including several checkpoints which control the number and activity of the types of cells that fight cancer. Each has positive and negative regulators. I contributed to the development of the first checkpoint inhibitor to be approved, Yervoy, which has been followed by agents such as PD-1 or PD-L1 blockers. There is a great deal of activity amongst the big pharmaceutical and biotech companies as they compete to bring the next checkpoint inhibitor to market. Yet these agents also have their shortcomings. They seem to be working in the same few cancers, though even where they work best, some 60% of patients don’t respond to treatment.

At Advaxis, we have seen where the checkpoint modulators are headed and understand where they will be limited. We are developing an immunotherapy platform that will be complementary to current immunotherapies and extend their activity to groups of patients who otherwise would not be reached.

As a demonstration of this, we have recently combined our technology with an anti-PD-1 checkpoint inhibitor antibody. This study was conducted in the laboratory of Dr. Samir Khleif, an expert on immunotherapy and cancer vaccines. The combined treatment led to significant inhibition of tumor growth and prolonged survival/complete regression of tumors in treated animals, a result that was not achievable by either treatment alone. These findings show that the two technologies have complementary mechanisms of action and were published in the Journal of ImmunoTherapy by Mkrtichyan, et al. (Journal for ImmunoTherapy of Cancer 2013, 1:15).

Why is this important? These checkpoint inhibitor therapies, like the ones tested by Dr. Khleif, rely on enabling the cancer fighting cells that the body already has produced, tumor specific T cells, that have been deactivated by negative signals, such as PD-1, which tell them to shutdown at key checkpoints. Blocking the signal with a PD-1 antibody can sometimes allow those T cells to proliferate and become activated again to fight the cancer. However, in some patients, those T cells may not have been generated to begin with, so blocking checkpoint inhibition with the PD-1 antibody doesn’t help. In addition, once the reactivated T cells enter the tumor, they can also be shut down by deactivating cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

When combined with a low dose of Advaxis immunotherapy, the PD-1 antibody tested by Dr. Khleif results in a significantly larger number of tumor-fighting T cells than seen with the Advaxis immunotherapy alone. These two immunotherapies synergize, as complementary technologies: the Advaxis immunotherapy makes sure the right cancer-fighting T cells are generated and neutralizes the tumor protection inside the tumors, while the PD-1 antibody takes the brakes off the growth of the T cells, resulting in a larger and more powerful cancer-fighting force.

As multiple companies vie for an advantage in competing for the future PD-1 market, the Advaxis platform’s ability to ensure the presence of tumor-reactive T cells plus its capability to override Tregs and MDSCs in the tumor microenvironment, and its versatility to be directed toward multiple tumor targets (Advaxis has developed over 20 different tumor antigen-targeted constructs so far), might capture the attention of a larger company with a PD-1 or PD-L1 blocking antibody that is seeking an advantage.

This is why I feel that if Advaxis continues to have clinical success, the possibility of a foreseeable future where more than 50% of cancer treatment includes immunotherapy will become a reality.

Thank you for reading this blog, we look forward to continuing to share updates with you.

 

Best,

Robert Petit

 

Dr. Robert Petit has over 25 years of experience in oncology drug development with a specific focus on Immuno-Oncology.

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