Taking the Next Step: What We’ve Learned About CAR-T So Far, and What It Means Going Forward

A year ago, flush with the excitement of the FDA approval of the first chimeric antigen receptor T-cell (CAR-T) therapy for acute lymphoblastic leukemia (ALL), the AACR Annual Meeting focused considerable attention to CAR-T. The approval marked a significant milestone in cancer treatment for researchers and oncologists, which supplied a new ray of hope for patients around the world.

Today, on the eve of AACR’s 2019 Annual Meeting, CAR-T is still at the forefront of everyone’s mind. CAR-T grabs a lot of headlines – from companies working on CAR-T (or buying companies working on CAR-T) to new regulatory approvals for use outside the U.S., but also to discussions about the challenges of CAR-T, including manufacturing, cost, and reimbursement. Innovations usually attract attention – and CAR-T attracts even more attention because it has proven it can work in some very challenging patient populations.

But given the aggressive pace of therapeutic discovery and development in oncology, it’s not too early to ask: What have we learned from the CAR-T experience with blood cancers? Can we translate that experience to other types of cancers, and what challenges still lie ahead?

From the perspective as a developer of CAR-T for solid tumors, I believe we are learning a lot from the liquid tumor experience. Some of this is accepting that CAR-T development can be more difficult than we expected; some is re-looking at aspects to reduce issues we initially anticipated.

For example, because of the intensive nature of monitoring patients with blood cancers, they are likely to be treated in hospitals or cancer centers where the administration of a complex CAR-T therapy can be more readily managed. The ability to perform a bone marrow transplant in a given center perhaps makes the complexity of CAR-T less daunting when performed in that center. Solid tumors, on the other hand, are less likely to be treated in these intensive care settings.

The challenge for us is simple – how to make the use of CAR-T less complicated and more accessible to the oncology community – while at the same time we have to use deep science and big data to solve a complex problem. While safety and efficacy is always the foundation, clearly we’ll have to pay attention – in advance – to streamlining the CAR-T treatment paradigm as much as possible; it’s not practical to expect we’ll be able to keep many solid tumor patients in an ICU for a week, or more.

At the same time, CAR-T for blood cancers has also shown us how to plan in advance for challenges in treating solid tumors, and possible ways to navigate around them. In a research hospital setting, the patient is almost literally down the hall from the “manufacturing site” of their own therapy. As we move away from that academic setting, we can see the importance of addressing predictability and consistency in blood collection and “manufacturing” – essentially creating a system that avoids bottlenecks in advance.

What we’ve learned from the first-generation efforts is that predictability is a crucial element of the CAR-T administration process; that when blood is collected, the oncologist knows when the product will be returned, which facilitates the needed pre-conditioning, dosing and preparation for patient care.  As a result, by developing CAR-T cell processes on electronic batch records, we may avoid a “bottleneck” by simplifying the blood collection process and returning it to the oncologist in a defined time frame. In the more distant future, the oncologist may not even send away the patient’s cells at all, nor have to decipher between febrile neutropenia and cytokine release syndrome in a patient that presents with an escalating fever.

But other more basic challenges remain for CAR-T in solid tumors. Achieving prolonged exposure of CAR-T products directed against solid tumors at blood levels found in liquid tumors is the starting point to answering many questions. Keeping CAR-T cells safely in circulation long enough without exhaustion or immunologic clearance to work their way through solid tumors is likely required to achieve deep responses.

Making CAR-T cells more resistant to the hostile microenvironment of many solid tumors will also remain a significant hurdle. Choosing cancer driving antigens for CAR-T development that are less likely to suffer from heterogeneity or antigen escape is yet another.

Potentially, innovations such as conditionally active biologics (CAB)-CAR-T technology and immune-checkpoint activated logic gates will allow us to use the negative aspects of the tumor microenvironment as accelerators of CAR-T signaling. By integrating these technologies into next generation CARs, we then may eventually drive efficacy levels towards that of blood cancers.

In a relatively short time since the first generation of CAR-T received approval, we’ve seen significant leaps forward in our practical understanding of this therapy. The first generation of CAR-T is showing us possible hurdles in the path ahead – as well as ways to streamline the process – facilitating new milestones in designing treatments that may change the lives of patients we all seek to help.

By: Gregory Frost, Chairman & CEO

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