shutterstock_486982282.jpgBernadette Bourjolly and Pranav Srivastava contributed to this blog post.

As I rounded the corner in the north tower of the Marriott hotel next to the San Diego Convention Center while attending the American Society of Hematology (ASH) Annual Meeting this past weekend, I was suddenly met by a sea of bodies straining to see ahead. Many were trying to push through, anxious to be on time for a main session on advances in immunotherapy for acute lymphoblastic leukemia. The ballroom was already full, and the ground staff was working feverishly to acquire an overflow room. One frustrated doctor next to me let out a sigh and said: “You think they would have learned from prior years. The CAR-T sessions need a main hall.” An overflow room opened next to where I was standing and I slipped inside, feeling lucky to grab a seat before the room filled and the process began again, causing many to miss some of the opening abstract presentation.


BLOG POST: ASH 2016: Have Combination Regimens Arrived Yet?

BLOG POST: Is the CAR-T Upset?

As my colleague suggested in his pre-ASH blog “Is the CAR-T Upset?,” we came to ASH curious to see if Juno’s recent toxicity challenges would put a damper on the excitement around CAR (chimeric antigen reception) T-cell therapies, or CAR-Ts. What we found was quite the opposite: continued high interest and packed rooms. In one of her talks on engineering T-cells beyond chimeric antigen receptor, Dr. Chiara Bonini estimated that the conference offered an impressive 120 abstracts with 42 oral presentations and 78 posters on CAR-Ts alone. We did sense an important shift, however, from pure excitement about the innovative revolution that CAR-T science sparked in earlier years to a push for a revolution in the approach to refine toxicity and increase overall success. At the end of the conference, we came home with three main takeaways:

1. Efficacy remains transformational. Since the beginning, CAR-Ts have created response stories that have given hope for science and, more importantly, for patients. And this time, too, CAR-Ts yet again demonstrated dramatically prolonged response rates in patients with relapsed/refractory disease in aggressive leukemias and lymphomas (papers 0217-0222, which can be found on the ASH website). Translation of encouraging preclinical data with CD123 CARs in Hodgkin lymphoma (paper 0043) and BCMA CARs in multiple myeloma (paper 081) is highly anticipated as well.

One question that arose from the audience on several occasions was on the reported response rate for these therapies: Should the overall response rate represent the intent-to-treat population, which would include those cleared as eligible but who do not get infused, or should it be the overall response rate of the infused population? The distinction in response rate observed in the ITT versus infusible population can have an impact on overall perception and, ultimately, bias expectations. As complex manufactured immunotherapies such as CAR-Ts change the nature of drug development and delivery, we’ll continue to encounter these types of questions and will need to establish accepted standards.

Complementing the story of efficacy, presenters of the several multicenter phase II trials with interim analysis all spoke to high rates of manufacturing success, overcoming another potential hurdle for development. For example, Stephan Grupp indicated that manufacturing failure in the global Novartis phase II ELIANA trial—with 25 sites across the world—was only 6%.

The only potential shadow looming on CAR-Ts’ efficacy is the persistence and durability of the response. Time will tell how these factors evolve.

2. Toxicities are under a microscope. The critical side effect of prior studies, cytokine release syndrome took a backseat to neurotoxicity in the discussions, likely a direct result of the recent focus on issues around toxicities like cerebral edema. There is limited understanding of the connection between the CAR-Ts’ administration to many of their side effects, but presenters spent more than an average amount of time on the toxicity profiles, careful to explain any events greater than grade 3, often in good detail. Presenters directly called out where such toxicities weren’t present as well, which, in at least one case, led to the question, “Why aren’t we seeing the same everywhere?”

Though we don’t know the answer, there were a number of talks around the different approaches being studied to manage the side effects, like using a combination of tocilzumab and anakira (paper 097) to optimizing the dose of CAR-T product infused, using lower doses or modified conditioning regimens, and finding markers that will let us address or predict the side effects proactively.

3. Evolution is taking many forms. Managing toxicity is good, but the call is really for evolution. How can we evolve the science to maximize efficacy and reach the 80%-plus survival rates seen in pediatrics while balancing a much greater safety profile? Many of the early CAR-T originators are already on it, presenting abstracts on next-generation products including humanized CAR-Ts (paper 0217), refined scFv affinity (paper 1627), the development of off-the-shelf therapies using gene-editing concepts (paper 0765), etc.

This came with concurrent research by many manufacturers and institutions looking to go even further with the potential of cellular therapies through alternate mechanisms [such as modified-TCR T-Cell therapies (paper SCI-13)] and, of course, extending targets beyond CD19 (for example, CD123, CD22, BCMA, CD33 and CLEC12A, to cite a few).

Even in Tuesday morning’s late-breaking abstract on KTE-C19, it’s apparent that the efficacy and potential for CAR-Ts remains strong (paper BA-6), and the race to market is still crowded. Durability will continue to be an open question.

While we’ll be monitoring these and the many other questions to be answered, as well as the evolutions to come, these therapies remain a great source of hope for many potential patients—and they are what these innovations are all about. 


Topics: Maria Whitman, CAR-T, immunotherapy, ASH 2016