John West

When an exome test is part of the therapy and not a diagnostic

Personalis CEO, John West, recently sat down with Mendelspod to discuss personalized cancer vaccines. Listen to the podcast or read the partial transcript below.

How are you participating in the recent wave of immuno oncology drug development?

Personalis is working with biotech and pharmaceutical companies to characterize the immune micro-environment of individual patient’s tumors. We do this by a combination of deep and highly optimized sequencing of DNA and RNA, and by use of proprietary data analysis methods. Our focus is on comprehensive characterization, what we call “The Immunogram”. This includes in particular the genetic variants which may lead to immune response, and other variants which may lead a tumor to escape that immune response. It also includes assessment of driver mutations, which led to a tumor in the first place. We are increasingly working with companies developing personal cancer vaccines, providing data and interpretation so that a vaccine can be synthesized on a completely custom basis for each individual patient. All of this work is done in conformity with the highest quality standards and in a regulatory partnership with our customers.

To explain this more thoroughly, and compare it with what other companies may be doing, let me back up and comment on how we as a field came to this position.

The concept of using the immune system to treat cancer dates to at least the 18th century, and there was a lot of work in the area starting in the 1970’s and 1980’s. In spite of that effort, the field was just not far enough along scientifically, and that work struggled to achieve success in the clinic.

In the meanwhile, during the 1990’s, as automated DNA sequencing was developed, researchers identified driver mutations in tumors which actually cause a cancer. These were in genes like EGFR, BRAF, ALK and others. Into the early 2000’s, pharmaceutical companies had multiple successes developing drugs to target these specific mutations. This led to the concept of companion diagnostics, genetic tests to determine if a particular patient’s tumor harbored the mutation which would make it susceptible to a specific drug. As of today, the FDA has approved 28 companion diagnostic tests, though several of those are for the same targeted cancer therapies. This came to be called Personalized Medicine, though the medicines themselves were not being personalized. Genetic tests, typically for variants in one or two genes, were used to determine if a patient’s tumor might be likely to respond to a specific drug.

While this wave of targeted therapies was being developed, work on cancer immuno-therapy continued. It had its first breakthrough success in 2011, leading to a new era quite different from the targeted therapy wave that preceded it.

  • In March 2011, the FDA approved a Bristol Meyers drug named Yervoy (ipilimumab) for use in metastatic melanoma. This drug blocks an immune checkpoint called CTLA-4, which normally prevents the immune system from attacking a tumor. By freeing up the immune system to do its job, some patients began to experience remarkable responses in some of the most deadly types of cancer.
  • In 2013, the journal Science called Immuno-therapy its “Breakthrough of the Year”.
  • Starting in 2014, drugs began to be approved which blocked an even more significant immune checkpoint, called PD-1, or its ligand PD-L1.
  • In Sept 2014, the FDA approved a Merck drug named Keytruda (Pembrolizumab), for late stage melanoma.
  • In Dec 2014, the FDA approved another Bristol Meyers drug named Opdivo (nivolumab), also for late stage melanoma.
  • In March 2016, the FDA approved a Roche drug named Tecentriq (atezolizumab), for advanced bladder cancer.

Together the revenue of these drugs has ramped to a rate over six billion dollars per year, a level which has more than doubled in twelve months. These drugs have been approved for additional types of cancer and many more are in clinical trials today.

The mechanism behind these drugs is different from the targeted therapies I described earlier. Genetic variations in a tumor are involved, but they do not have to be the cause of a tumor and in fact most are not. These mutations lead to abnormal proteins in tumor cells. When those proteins are broken up by the proteasome, they can lead to abnormal peptides being presented on the outside of a cancer cell where the immune system can recognize them. If a T-cell is activated by one of the peptides, it can lead the immune system to attack the tumor. Peptides which do so are called neoantigens.

It is important to understand that neoantigens can come from almost any of the 20,000 genes in the human genome, not just the driver genes that led to growth of the tumor in the first place. As a result, when we perform DNA sequencing to find these variants, we use an exome to look at all of the genes, not a panel as has traditionally been done in the world of targeted therapies. This means that we have to look at 20,000 genes, instead of just a few hundred.

It is also important to understand that only a tiny fraction of genetic variants in a tumor will lead to an immune response. This is because not all peptides can be efficiently bound by the MHC complex, and not all of those bound activate T-cells. Personalis goes beyond just the sequencing and identification of variants, to characterize which neoantigens might actually lead to an immune response.

By the time that a tumor metastasizes, it is often under attack by the patient’s immune system and its has developed mechanisms to escape from that. Understanding these escape mechanisms is also important to understand, and ultimately predict, which neoantigens may be antigenic. Personalis goes beyond neoantigen characterization, supplementing that with analysis of tumor escape mechanisms.

Analysis of the neoantigens and tumor escape mechanisms can help our customers understand why some patients respond to checkpoint inhibitors, and others do not. More importantly, it allows us as a field to take the next step, developing therapies which are optimized for an individual patient’s tumor immune environment. Some of these new therapies are used to supplement the work of checkpoint inhibitors and others are used as monotherapies. One of the most exciting of these are Personalized Cancer Vaccines.

What are personalized cancer vaccines?  How is the field developing?

We know from clinical trials that only a fraction of patients respond to checkpoint inhibitors, and not all of those responses last. Some patients though, do have responses lasting many years. This tells us that if the immune system is properly activated and if it develops an immune memory of the tumor, then it can provide a defense against the tumor over many years.

We know that immune response to many diseases can be dramatically improved by the use of vaccines. If these are administered before the onset of disease they are considered preventative vaccines, and if they are administered after the onset of disease, they are considered therapeutic vaccines. Personal Cancer Vaccines are therapeutic vaccines. They are used to stimulate immune response to a tumor’s unique neoantigens, by exposing the immune system to artificially synthesized replicas of those neoantigens.

To create such a vaccine, DNA from a patient’s tumor must be sequenced to identify potential neoantigens. Once these are prioritized for their potential antigenicity, a custom vaccine is synthesized for that patient, replicating in greater quantity the most potent neoantigens of that patient’s tumor.

A growing number of biotech companies are developing these vaccines and Personalis is working with them. We receive tumor samples from patients in clinical trials, sequence them in our clinical laboratory, and identify the expressed somatic variants. Recently, we have introduced additional bioinformatics, what we call a Neoantigen Pipeline, to predict the novel peptides which may be generated by the DNA variants, and to project their potential to stimulate an immune response.

Several of our customers have been approved for Phase 1 clinical trials of Personal Cancer Vaccines, and Personalis began processing these samples last year.

What can we look forward to from Personalis?

With its customers, Personalis is at the forefront of immunotherapy development. We have partnered in the development of autologous immuno-therapies, personal cancer vaccines, and other approaches.

While the interaction between therapies and the tumor micro-environment is complex, dynamic and personal, we believe it holds enormous promise and we look forward to helping advance the field.

One element of this is regulatory compliance. While the technologies we use are complex, including Next Generation DNA and RNA sequencing, neural networks and peptide characterization, we believe that they can be conducted in a Quality Management system appropriate for regulatory oversight. Personalis began development of its Quality Management system in 2012 and our laboratory is now CLIA licensed and CAP accredited. We have been working towards additional regulatory goals and anticipate additional progress in 2017. We see this as essential to our partnership with biotech and pharmaceutical companies and strive to be ahead of the curve in supporting their programs.

As we move through 2017 and 2018, we expect many of our customers to advance into later-stage clinical trials, and we look forward to that data. If these trials experience the success we hope for, regulatory approvals may come on the horizon and we may be able to make an even wider impact in the field of oncology. While checkpoint inhibitors have made a great step forward, we think that even greater successes are possible, and likely, in immunotherapy. Personalis plans to be an integral part of that advancing understanding and increasing personalization.