A few folks kindly emailed to point out that I had not mentioned the Memorial Sloan Kettering Cancer Center (MSKCC) in my previous post. The sin of omission. Apologies, but I’ve been trying to digest the press release that the MSKCC put out on February 19th. The presser served two purposes I think, one valid (here’s some data) and one just pure PR grandstanding. Plus, the release didn’t link to the actual study. That was published in Science Translational Medicine the same day as I found out after some text searching, only to run into a paywall.
So, here is the referenced paper:
Davila ML et al. 2014 Efficacy and Toxicity Management of 1928z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. Sci Transl Med. Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
The data from MSKCC investigators (the PIs are Renier Brentjens, Isabelle Rivière, and Michel Sadelain) is very impressive. In a small phase 1 study of patients with relapsed of refractory Acute Lymphoblastic Leukemia (r/r ALL), patient T cells were transduced with the CAR construct 19-28z CAR and reinjected into the patient. As seen with CTL019 (previous post), this is an effective strategy for producing a lasting T cell response to the CD19-positive leukemia. In the 16 patient trial, 88% of patients responded and just under half went on the receive allogenic HSCT, the standard of care for ALL. So thats great. Just to add some details, a complete response (CR) was reported for 14/16 patients. Two of these patients were already minimal residual disease (MRD)-negative when enrolled. The MSKCC study defines MRD- patients as CRm. The CRm is given as 75% so I’m guessing here that the 2 patients already MRD- at enrollment were not re-counted. Of these 75%, one third were further defined as CRi (CR with incomplete cellular recovery) meaning that they were cytopenic for one or more cell types. Other than this reference to toxicity, the paper generally focuses on cytokine release syndrome (CRS), noting that CRS can be accurately tracked using the routine clinical laboratory marker CRP. More importantly the investigators use a cytokine panel and CRP to define a severe CRS (sCRS) group of patients and a non-severe (nCRS) group of patients. Please note here that if you take the time to burrow through the supplemental tables you will find that both sCRS and nCRS patients had grade 3 and 4 adverse events including hypotension, febrile neutropenia, hyponatremia and altered mental state (CNS toxicity). sCRS patients (7/16 = 44%) further presented with fatigue, atrial fibrillation, sinus tachycardia, electrolyte imbalance, hypoxia and respiratory failure. It’s an important distinction, as the sCRS patients remained hospitalized, including ICU care, for an average of 57 days, versus 15 days for the nCRS group. Both groups are incurring very high health care costs post-treatment.
19-28z CAR differs from CTL019 in several interesting ways. The extracellular domain is a CD19-specific scFv. This is genetically linked to transmembrane and cytoplasmic domains from the costimulatory protein CD28, linked in turn to the CD3 epsilon signaling motif. CTL019 is similar overall, but uses 4-1BB domains instead of CD28 domains. One important consequence of the use of CD28 versus 4-1BB as the costimulatory effector domain is the persistence of the expanded T cell population after injection into the patient. For the 19-28z CAR T cells described in the present paper, the average duration was 3 months. The authors suggest that this is shorter than the duration seen with CTL019 treatment, and that this may be beneficial. That remains to be seen, as we really need duration of disease remission data to understand the benefit/risk of maintaining the T cells that control the leukemia. A final note on this: the MSKCC investigators go to some lengths to sketch out a clinical development plan that can be applied to various centers (not just theirs). This is a very important and useful development, which we would hope make these cellular therapies more widely available.
On the basis of this early data presented here and the phase 2 data coming from the U Penn group (see the prior post), its safe to say that we are watching the development of a new standard of care for ALL patients.
Back to the presser for a moment. The rest of the press release was amusing in a ballsy kind of way. There was the breathless prose and the very pointed “we were the first” claims that science journal editors (but not PR directors) generally avoid. As we all know, none of this science developed in a vacuum and the claim of precedence will be sorted out by patent courts as necessary. For the record I really have nothing against their PR campaign, it just makes me squirm a little. I happily support the MSKCC every year by donating through their Cycle for Survival Program (thanks to the strong legs of longtime friends John and Susan Canavari). Also I really look forward to watching this technology develop, along with technology from the Fred Hutchinson Cancer Center and the Seattle Children’s Research Institute, under the umbrella of Juno Therapeutics, which was formed in Seattle in December specifically to advance this and related therapies.
It’s pretty clear that this technology is very important and very very exciting.
Now, why don’t these cell based therapies work as well in other indications, like Non-Hodgkin lymphomas?