Driving CAR T Cell Therapy

How did you find your way into CAR T cell therapy?

I joined Amgen in 2002, supporting a range of biomarker development programs spanning inflammation, metabolic disorders, oncology, and more.

In 2015, I came to Kite, where I focused on developing a translational strategy to support the development of Yescarta® (axicabtagene ciloleucel, a CD-19 CAR T cell immunotherapy). My initial experience at Amgen allowed me to blossom into a translational role at this much smaller company, where I am now a Director in the Translational Medicine Group.

What is the Translational Medicine Group?

What we do – everything from clinical pharmacology to correlative analysis – would traditionally be covered by multiple teams in a larger pharma company. Having intimate knowledge across many areas has allowed us to support the key functions within the Cell Therapy Division, and we work very closely with many different parts of the organization. Currently, we are characterizing the mechanisms of resistance, relapse, and toxicity so that we can better manage our patients.

Our multifunctional team is really a legacy of where we started: a small start-up company that required each of us to wear many hats. As the company grew, the Translational Group continued to manage these responsibilities. The initial model has been maintained through time. And we’re proud of that.

What are the drawbacks of the current generation of CAR T cells?

The most recent data show that 40 percent of our patients are in remission after two years, and the overall response rate is 80 percent. The next generation of products will serve the 30 percent or so of patients who relapse due to losing their targeted antigen. I don’t think we are able to talk about a cure yet, but that is the ultimate goal.

Neurologic toxicity is a big issue that we need to figure out and control. About a third of patients experience notable neurologic events. These are currently managed with corticosteroids, but a greater mechanistic understanding will allow more targeted interventions.

What are the main challenges in developing new cell therapies?

Any expression of a target on normal tissue allows CAR T cells to cause damage. We need to identify better non-essential targets, a task that has proven to be a huge challenge to the field. An alternative is currently being investigated: using engineered T cell receptors to target an HLA-presented peptide restricted to the tumor.

The next challenge is to overcome barriers in the tumor micro-environment. We hope to engineer the next generation of cell therapy products to counter checkpoints, myeloid-derived suppressor cells, and regulatory T cells.

Kite has a trial program, in partnership with the National Cancer Institute (NCI), to further identify and develop unique T cell receptors. We use strategies such as synNotch – synthetic biology based on a logic system that requires two antigens to activate the T cell. The cells would also be engineered to express tethered IL-15 to bring a cytokine that would promote proliferation of that T-cell product within the tumor microenvironment.

We are also thinking about partnering with Gilead to use different molecules to reprogram the tumor microenvironment so that is more permissive to T cells.

How far away are we from the next generation of therapies becoming reality for patients?

In oncology, we should see some of the combination studies within the next three years, and cell engineering after that. We are close, but it takes time to really figure out how to maintain the added functions without losing the T cell’s ability for cell killing. We may be able to see the successes of these futuristic, next-generation products sooner if we invest properly and pick the right targets and approaches.

We have come from single-center trials treating 10 to 20 patients and now treat thousands of patients both in the US and Europe. We continue to learn, accelerating the development process. 

Additionally, cell and gene therapies are going to continue to improve and advance different medical conditions such as thalassemia and other blood disorders. We will soon see cell therapies for immune disorders. The future is very bright for all areas of engineered T cell therapy.

Where will oncology treatment be in 20 years’ time?

I believe in my heart of hearts that we are going to use off-the-shelf progenitor stem cells engineered to target cancer cells and overcome the tumor microenvironment. Off-the-shelf therapies will reduce costs and increase access to a great number of patients. It will take time, but it’s where we are headed – Kite has an active program in that area.

It is also crucial that we continue to invest in academic science that seeks further advances. Kite is sponsoring numerous studies, providing funding and samples to some of the best and brightest in the field. We hope that governments around the world will continue to invest in basic research that is ultimately going to drive these next generation therapies.

Can you give an overview of some of your most recent research?

We have been investigating pre-existing inflammation within the tumor microenvironment and how that relates to critical outcomes for CAR T cell therapy; those patients with less widespread disease and whose tumors have a pre-existing cytotoxic infiltrate (“hot” tumors) tend to have a better response rate. And that tells us that earlier lines of CAR T cell therapy may increase the overall response rates and reliability, and we should consider strategies to convert a “cold” tumor to a “hot” tumor. 

We have also been looking at vector integration sites using the retrovirus from CAR T cell therapy manufacturing. The goal of the study was not only to characterize the integration site, but to convince ourselves – and the regulatory agencies – that the virus provides a low risk for secondary malignancy in patients. We found that the integration sites are highly variable across patients. But importantly, there weren’t any clones that particularly expanded out during manufacturing. A competitive growth advantage could have led the clone to transform into a T cell leukemia layer, for example. This is nothing new, and is consistent with the literature. But this is a significant study, as it characterizes the integration patterns and safety profile of the retroviruses used to manufacture our T cell. And it should help to lift the fear of gene editing.

To what extent should cell and gene therapies be combined in one field?

Gene and cell therapy approaches are intertwined. Cell therapy without any genetic engineering has shown some success, but gene editing will continue to be heavily used to advance cell therapy. Next-generation products are really going to rely on gene therapy approaches to make a T cell product highly effective across a number of different cancer indications.

What key lessons will inform future treatments?

The first lesson is critical: developing a robust, easy, streamlined manufacturing process that consistently produces an efficacious product. It’s hard to scale up! The process we have developed for anti-cellular CAR T cell therapy consistently yields a product, with a relatively quick turnaround time of 17 days – critical for very sick patients. Manufacturing prowess and know-how are at the core of autologous cell therapy, as the technology currently stands. 

The second lesson was not an easy one. A multiple myeloma program was terminated early because we didn’t feel that our product was better than the products already in clinical trials. We learned that it is in no way trivial to develop a next-generation product to beat the success that we have with current CD-19 CAR T cells (which had been development for about 30 years prior to approval).

Kite’s next product will benefit from both these lessons. We know what works and also what doesn’t work, and we will continue to build on that.

How is Kite’s work benefiting patients?

Our work is transformative. Cancer patients who were given three to six months to live are now back with their families, back at work, and have healthy, normal lives. Even patients who relapse are able to have more time with their families.

There is still progress to be made. Cancer is a tough beast, but this generation of CAR T cell therapies are helping people across the US and Europe, and hopefully soon the rest of the world.