Interview with Dr. Ken Culver, ALK Positive, Inc. Director of Research & Clinical Affairs

1. Tell us a little about your personal and professional background, and what inspired you to accept the position of Director of Research & Clinical Affairs for ALK Positive, Inc.

I became a medical doctor because I sincerely wanted to make a meaningful difference in people's lives. The University of Iowa gave me a fantastic medical education. I moved to the University of California San Francisco (UCSF) for my pediatric internship and residency. That terrific program was where I learned how to provide care from a holistic view to help children become healthy adults. Subsequently, I completed a fellowship to become Board-certified in immunology.

As part of my training at UCSF, I worked in a pediatric bone marrow transplant unit caring for children suffering with terminal genetic and malignant diseases. We were trying experimental treatments in these desperate circumstances that too often failed. That motivated me to pursue a career as a physician-scientist to see if I could do something to stop children like these from dying.

Gene Therapy Press Conference on Sept. 1990. Pictured L to R: Dr. Michael Blaese, Dr. Andersen and Dr. Kenneth Culver. Credit National Cancer Institute.

So I left California to work at the National Cancer Institute (NCI), at the National Institutes of Health (NIH) in Bethesda, MD. There I worked on a team developing gene therapy for children with a type of “Bubble boy disease” called adenosine deaminase (ADA) deficiency. Mutations in the ADA gene resulted in the children not having a functioning immune system. Injections of the ADA enzyme had been developed to help protect them from opportunistic infections but was not curative.

Our laboratory research led to the first ever human gene therapy trial for the treatment of children with ADA deficiency. On September 14th, 1990, I had the privilege to administer the first of multiple of genetically engineered T-cells to a four-year-old girl. She is alive today, a college graduate, and married. Six weeks after the first infusion, her father called me to say that she had not had any infections in the last 6 weeks, the longest infection-free period in her life. A second child began treatment in 1991 and she has done well too! The team that I was a part of started the new area of genetic therapy. This experience was especially motivating, and it demonstrated the true power of medical research.

Working at the NCI, we devised an experimental gene therapy for glioblastoma multiforme that went into clinical trials. While patients could have long responses, the overall response rate was low, so the program was terminated. For me personally, this is when my career started to focus on oncology.

To contribute to the larger global population, I started working at Novartis Pharmaceuticals in 1998, where I stayed for 20 years. While there, I had the honor to work on 12 oncology drugs, six of which were approved by the FDA, benefiting thousands.

One of those was Ceritinib (Zykadia), the second FDA-approved ALK inhibitor. It was through the development, FDA approval, and work to make the drug available to patients worldwide that I got to know the ALK positive patient and physician community. Knowing the history of ALK drug development and the inspiration of ALK patients made it easy to accept the offer to join ALK Positive Inc.

2. What do you see for the future of ALK research? What are some of the biggest opportunities, and what are some of the biggest challenges in your opinion?

There are so many reasons to be optimistic about success in developing new therapies for ALK-positive cancers. One of those is how ALK Positive, Inc. is advocating for and succeeding in bringing clinical trials to ALK patients. That to me is extremely exciting!

It is important to keep in mind that the development of new treatments is linked to the development of therapies for other cancers. Ideally, new treatments for ALK would be active for other cancers as well, increasing the number of patients who can benefit from them and making drug development in NSCLC sub-types more appealing for commercial companies. With that as a goal, we must also be simultaneously looking for opportunities that are ALK-specific, as has been the case with the tyrosine kinase inhibitors.

One of the biggest challenges, in my opinion, is figuring out how to eliminate all cancer cells with the very first treatment. Then we do not have to deal with the issues of resistance and long-term side effects of the therapy. While that is an aspirational goal, we should not deviate from it.

Currently, the development of resistance to TKIs in ALK NSCLC is a primary issue. Unfortunately, the cause is multifactorial and complicated. With new molecular profiling techniques, we believe we are going to be able to unravel these complicated pathways and perhaps develop new therapies that are independent of the pathways of resistance to TKIs. Just because PD-1 checkpoint inhibitors failed to show activity in ALK NSCLC, does not mean that other immunotherapies will not be active. We have evidence from pre-clinical studies that the immune system can be activated to kill ALK-positive tumor cells. This gives me real hope for new immunotherapies in the next five years to complement TKI's.

Cynthia and Ashanthi in 1992 with the pioneer physicians of gene therapy (from left) French Andersen, MD; Michael Blaese, MD ; and Kenneth Culver, MD

3. Are there any new treatments or therapeutic options currently in development or in clinical trials that get you excited about the future of ALK-positive cancer?

Fortunately, there are a variety of new potential treatments for lung cancer in development. These include differing methods to target proteins, RNA, DNA, bacteria, immune cells, and other parts of the oncogenic process.

We are excited to be supporting the Judith Tam ALK Lung Cancer Research Initiative at the University of Michigan. The team at the University of Michigan is looking at multiple aspects of the ALK cancer cell journey from the beginning when ALK-positive tumors are initiated, to molecular characterization of the associated genomic drivers, to new therapeutic development and then translation into clinical trials. Members of the ALK Positive Inc. Medical Committee are happy to be included on their scientific advisory board (SAB) and to be able to create opportunities for the testing of additional agents in their mouse model systems.

One new possibility is combining ALK TKI's with a CD47 inhibitor. CD47 is a cell surface receptor on macrophages, a type of white blood cell that can kill cancer cells. The CD47 receptor is also called the “Don't eat me gene” because inhibition of CD47 causes the macrophage to destroy or “eat” tumor cells. A recent journal article demonstrated that adding Lorlatinib to a CD47 inhibitor dramatically increased tumor killing beyond either agent alone. Multiple companies are developing CD47 inhibitors. ALK Positive Medical Committee members are engaging with every company to see how we can expedite clinical trials with the combination.

Every week the Medical Committee members are reviewing papers, congress presentations and any other information we can find, to make sure that we are following up on all opportunities to develop new drugs for ALK cancers.

This is just an overview of the kinds of things that the ALK Medical Committee with all its sub-Committees are doing. I am extremely impressed with the patient and caregiver members of our Medical Committees and how they are translating their sense of urgency to activities that we believe are going to expedite new treatment opportunities for ALK patients.

4. What can the patient and caregiver community of ALK Positive do, if anything, to accelerate the pace of any new therapies coming to the clinic faster?

Fortunately, there are a multitude of ways for patients and caregivers to get directly involved to help this process. Here are few examples:

1. Understanding the ALK patient journey:

a. Personally keep all your information up to date in the longitudinal registry and encourage others to do so. Without accurate and complete information, the value of the registry will be diminished.

b. Participate in an ALK NSCLC patient preference study to help oncologists and pharmaceutical companies better understand what matters most to patients.

2. Help us to understand the mechanisms of progression on TKIs:

a. Provide blood and tissue samples to ALK research centers to help understand the biology of resistance, enable screening of new drugs that might be active and guide the development of new therapies to overcome resistance.

3. Help develop new tests to improve care:

a. Volunteer to provide tumor tissue samples such as blood, tumor, and cerebral spinal fluid (CSF) to help develop new biomarkers for informed patient care.

b. Provide blood samples to develop new biomarkers that can identify progression before scans do.

4. Educate and Motivate:

a. Deliver API educational information to oncologists to keep them informed on the evolving treatment and diagnostic landscape for ALK positive lung cancer.

b. Ask oncologists to pass along information on the longitudinal registry to their other ALK patients.

c. Keep yourself informed, on the lookout for new opportunities to improve the quantity and quality of life for patients with ALK- positive lung cancer.

d. Educate your community on why donating to ALK-positive research is changing lives. We have a remarkable story to tell about how TKI’s have been so successful, but the work is not yet complete. We need to find the elusive cure.

5. Have a plan in place to make the most out of your tumor:

a. Have a treatment plan in place, so when progression occurs you have a framework for action

b. Consider joining a clinical trial that may improve your quantity and quality of life and contribute to research that may help thousands more in the future.

Interview by: Christina Weber