Immunosequencing for Cancer Immunotherapy Development

Ann Nguyen:
Hello. My name is Ann Nguyen, Senior Associate Conference Producer at Cambridge Healthtech Institute. Today we have a special podcast focused on immunosequencing and cancer immunotherapy with Dr. Catherine Sanders, Director and Team Lead of Scientific Liaisons at Adaptive Biotechnologies.

Catherine, thank you for joining us. How are you today?

Catherine Sanders:
I'm doing well, thank you.

Ann Nguyen:
Interest in cancer immunotherapy has surged dramatically over the past few years with numerous bi-techs formed, and significant efforts initiated by both academic and industry researchers. Adaptive Biotechnologies has emerged as a major player in this space. Can you tell us a bit about Adaptive Biotechnologies, its origins, and where you are as a company now?

Catherine Sanders:
Absolutely. Adaptive Biotechnologies's original immunosequencing technology was developed at Fred Hutchinson Cancer Research Center by Harlan Robins, Chris Carlson, and Hootie Warren. When their first methodology manuscript was published in Blood in early 2009, they had so many requests by other researchers to utilize their immunosequencing assay that they decided to go ahead and spin out a company. Adaptive Biotechnologies was actually founded in late 2009, and we started accepting samples commercially in early 2010. Since its inception, Adaptive has received its CLIA license as well as its CAP accreditation. We did acquire a competitor called Sequenta in January of 2015. To date, we've actually raised more than $400 million in capital to really further grow the company, to launch a diagnostics business, as well as to launch a therapeutic branch of the company.

We have grown to more than 250 employees. We're now partnered with more than 60 pharma and biotech companies. We're actively involved in more than 100 pharma-sponsored clinical trials. To date we have more than 140 publications in high-impact journals like New England Journal of Medicine, Science, and Nature.

Ann Nguyen:
Immunosequencing is somewhat of a new concept for scientists in this space, yet it has incredible research and clinical utility. Can you please tell us about immunosequencing and its applications in preclinical and clinical settings?

Catherine Sanders:
Immunosequencing is the science of profiling lymphocyte receptors by combining multiplex PCR, high-throughput sequencing, and sophisticated bioinformatics. Specifically, Adaptive focuses on the complementarity determining region 3, or CDR3 region of the T or B cell receptor. Antigen specificity of each lymphocyte is actually in large part determined by the amino acid sequence of this particular CDR3 region, and by profiling these dynamic receptors utilizing Adaptive’s immunoSEQ Assay, we can track specific clones over time, assess the diversity of the adaptive immune system, and evaluate the immunologic response to antigenic stimulation.

The applications of the technology range from autoimmune disease to oncology to hematology, transplantation, and infectious disease. In preclinical trials, investigators are really using immunosequencing to evaluate mechanism of action or immunogenicity of certain compounds. For instance, does a drug have a targeted mechanism of action in tissue, or does a drug elicit a systemic immunologic response?

Additionally, the technology can be used in preclinical settings to determine which drug combinations are more synergistic, so essentially we can evaluate the immunologic response to monotherapy versus combination therapy, and then in relation to combination therapy, we can look at concurrent therapies versus sequential therapy to see which therapies are more effective.

Then in the clinical setting, investigators are utilizing immunosequencing technology for biomarker discovery, including biomarkers of disease, biomarkers of response to certain therapeutics, and biomarkers of toxicity to compounds. Additionally, Adaptive has developed an immunosequencing assay in the diagnostic space, which is utilized to monitor minimal residual disease in lymphoid malignancies with a sensitivity of 1 in 1 million cells, so this surpasses flow cytometry technology where the sensitivity is roughly 1 in 10,000. Really, the immunosequencing technology is utilized in preclinical trials, Phase I, Phase II, as well as Phase III across a variety of different settings.

Ann Nguyen:
You are giving a luncheon presentation during the Cancer Immunotherapy and Combinations meeting June 15-16 in Boston. Can you give us an idea of what you hope to convey to attendees during this lecture?

Catherine Sanders:
Adaptive Biotechnologies will be giving a capabilities presentation at the upcoming Cancer Immunotherapy and Combinations meeting. Dr. Sharon Benzeno, who is our vice president of business development, will give a brief overview of our immunosequencing platform, and then she'll start to show data generated specifically in immuno-oncology. Data will include capabilities to identify synergistic drug combinations, biomarkers of response to immunotherapy, as well as biomarkers of toxicity all based on immunosequencing data generated from tumor infiltrating lymphocytes as well as peripheral blood samples.

Ann Nguyen:
Finally, we value your opinion regarding the outlook for immunosequencing as it relates to cancer immunotherapy. What challenges exist that may be overcome in the near future, and what does the future of Adaptive and immunosequencing look like?

Catherine Sanders:
Many new cancer therapies are immune modulating in nature. Of course, immunotherapy targeted therapies, even cancer vaccines and new cellular therapeutics like adoptive T cell therapy. There's really a strong need for an immune biomarker to really reliably predict response to these different treatment modalities. It looks like tumor infiltrating lymphocyte assessments are emerging as one of these potential cancer biomarkers.

Adaptive's immunosequencing platform is really advancing both the diagnosis and treatment of cancer in several clinically impactful ways, including advancing basic cancer research by enabling scientists and researchers to elucidate immune-related mechanisms of disease and treatment, by accelerating pharma companies' efforts to incorporate our assay into clinical trial to really predict efficacy and safety of these cancer therapeutics. We're doing this with an assay called The immunoSEQ Assay, which accurately quantifies the density and clonality of the tumor infiltrating lymphocyte populations in both preclinical and clinical settings. We have the ability to track clones from the tumor into the peripheral blood. We've actually been able to identify blood-based biomarkers for certain checkpoint inhibitors based on the tumor infiltrating lymphocyte populations that are present in the blood.

Additionally, we've been able to identify biomarkers that can segment patients into groups of responder versus non-responder based on baseline immune infiltrates within the solid tumor microenvironment. For some therapies like anti-CTLA-4, which are known to be very toxic, we've been able to identify potential biomarkers of toxicity, so essentially if you could identify these patients who are going to develop toxicities ahead of time, you could change the clinical management of that individual and perhaps prevent that toxicity from actually occurring.

Ann Nguyen:
It sounds like there's a lot of exciting and very important work going on.

Catherine Sanders:
Absolutely. We're really better stratifying patients by identifying responders, really selecting lines of treatment that will be more successful. We are utilizing the technology to identify the optimal dose for certain immunomodulatory compounds, predict adverse side effects due to systemic responses, so really the applications are manifold.

Ann Nguyen:
With that, I think we'll wrap up. Catherine, it was a pleasure speaking with you. Thanks so much for sharing your thoughts today, and we look forward to you and Adaptive joining us during one of our upcoming Cancer Immunotherapy meetings.

For those listening, thank you for tuning in. Goodbye!