Thoughts on Bluebird's Striking BCMA CAR-T Data

Bluebird bio just released early data from their initial first-in-human trial of a BCMA CAR-T product for multiple myeloma that will be presented tomorrow at the #ENA2016 meeting. This is a 2nd generation 4-1BB CAR targeted to BCMA with a cyclophosphamide + fludarabine based conditioning regimen. The early results are quite impressive, with a 78% response rate in all 9 patients evaluable for response, and 100% in the 6 patients treated at the two highest cell doses. Even more impressive, and surprising, has been the lack of grade 3 or higher cytokine release syndrome or neurotoxicity that is frequently observed in CD19 CAR trials, as well as other BCMA CAR trials. While this data is still very early, with only 11 patients treated, dose escalation ongoing, and less than 1 year follow-up, the results compare very favorably to other BCMA-directed CARs, which I'll compare below.

Here is the data from Bluebird's press release:

The time to response seems a bit slow (2 & 4 months) so it's possible that some of the PRs in the highest dose cohort will improve with further follow-up. They also mention that all patients in the two highest dose cohorts that had detectable MM in bone marrow had no detectable MM in bone marrow by day 14 and beyond. They do not mention if any of the patients have relapsed, although the wording regarding the sCRs suggests that they have not relapsed at 4 and 6 months follow-up.

These data compare favorably to a 4-1BB BCMA CAR being developed by UPenn/Novartis that had some preliminary data on 6 patients in their recent ASH abstract. In this first cohort, they did not lymphodeplete with conditioning chemotherapy prior to CAR-T infusion. Even without lymphodepletion, they were able to get significant expansion of CAR-T cells in two of the six patients. These two patients also had significant responses - a VGPR and an sCR, with the sCR ongoing at 7 months, but the patient with the VGPR relapsing after 5 months. They administered a similar number of cells as Bluebird, 1.8-5 x 10^8 cells. Importantly, both patients who responded, and had significant expansion of CAR-T cells, also had grade 3 cytokine release syndrome, and one of the two had grade 4 reversible neurotoxicity. CAR-T cells were found in the CSF of this patient. This data is summarized in the table below:

These results were fairly similar, but perhaps more variable, than results published from a clinical trial on an earlier CD28 BCMA CAR at the NCI. In this study, they dose escalated up to 9x10^6 cells/kg and were given conditioning chemotherapy of cyclophosphamide and fludarabine. They treated 12 total patients, with both patients treated at the highest dose having responses of greater than 8 weeks (sCR of 17 weeks and VGPR ongoing at 26 weeks). Patients treated with lower doses of CAR-T cells had either no response, or responses of shorter duration.

From Ali et al., 2016

Importantly, similar to the UPenn study, it was the patients (10 & 11) that had the most dramatic expansion of CAR-T cells that had significant clinical responses:

From Ali et al., 2016

It was also the two patients with these dramatic expansions of CAR-T cells that had CRS and neurotoxicity (reversible).

Thus what is surprising is that the patients in Bluebird's trial achieved significant responses without these significant toxicities. This is quite different from both the UPenn trial and original NCI trials, where activity came with grade 3 and higher CRS and/or neurotoxicity. I'll discuss this difference further below.

These trials also began to characterize relapses after initial responses. In CD19 CAR trials, relapses frequently fall into two categories - loss of the target antigen (CD19) or (/and) loss of persistence of the CAR-T cells. Loss of antigen expression/availability is a concern for all CAR-T therapies. In UPenn's trial, one patient relapsed with loss of BCMA expression and concomitant loss of CAR-T persistence. The patient with an ongoing response still had detectable CAR-T levels. A patient in the NCI CD28 BCMA CAR trial who had a transient response also was found to have lost BCMA expression on their MM cells, but a number of patients who relapsed were not evaluable for BCMA expression, so this may be an underestimation of antigen loss frequencies. Importantly, in this trial, the CAR-T persistence was fairly poor, with loss of CAR-T persistence by 3 months, which could also partially explain the transient responses. The general thinking seems to be that 4-1BB CAR-T cells have better persistence, and CD28 CAR-T cells have greater expansion (and perhaps greater toxicity).

Bluebird will present their data tomorrow, so we should get some additional details.

Questions I'm thinking about going into their presentation:

What was the disease burden in their treated patients? Lower disease burden may cause less CAR-T cell expansion and toxicity. In the NCI trial, both responding patients had bone marrow disease burdens of >80%, and in the UPenn trial, both responding patients had bone marrow disease burdens of >70%.

What were the kinetics of tumor response? What was the speed of decreases in tumor biomarkers and soluble BCMA levels - these decreases were fairly rapid (on the order of weeks) in the NCI trial.

What were the kinetics and peak of CAR-T cell expansion? Did the cells expand to less dramatic levels, or less rapidly, than in previous BCMA CAR-T trials, but were still able to induce responses?

How well do their CAR-T cells persist over time?

What was the state of their CAR-T cells at peak levels? %CD8+ T cells and levels of activation markers.

How are the conditions different (if different at all) for how Bluebird manufactures their T cells compared to others? What is the composition of their final product in terms of T cell markers? At last year's ASH they had presented their finding that adding a PI3K inhibitor during manufacturing led to better efficacy preclinically.

How durable have the responses been? Bluebird started treating patients in February, and the data cutoff for the abstract was November 18th, so I am not expecting a lot of data to answer this question.

Have there been any relapses, and have these been associated with antigen loss or loss of CAR-T persistence (perhaps at the lower dose levels)?

*Update 12/1
Bluebird presented their data in a conference call this morning. Slides of their presentation are available here.

Of the above questions, Bluebird mainly presented data on the initial kinetics of CAR-T cell expansion and tumor marker decrease, as well as cytokine levels. They did not, however, want to speculate on differences between their trial and other BCMA CAR-T trials, and did not appear to provide any additional information on the initial tumor burden levels in these patients. They also did not characterize the T cell product for CD4:CD8 ratios or other T cell markers either prior to infusion or during treatment. They did not want to speculate on manufacturing differences between their product and others, but mentioned they plan to bring along their next generation BCMA-CAR program, which will use the PI3K inhibitor during manufacturing over the next year.

Below are some of the key additional data they presented. While they did not want to compare data too closely to other BCMA CAR-T trials, I will make some very preliminary, premature, any other diminishing adjective you want, comparisons just to start getting a sense of some of the early similarities and differences. Of course, this is all subject to change with further follow-up and additional patients, so CAUTION is warranted when trying to draw any conclusions.

Response timing and durability:

Above, you can see the time to first response and time to best response in their treated patients, as well as time to disease progression. In the first three patients treated at the lowest dose level, only one achieved a PR, and then subsequently relapsed after >12 weeks, but they did not disclose any data on the nature of this relapse (although persistence of CAR-T cells was shorter for this dose level, as shown below). Another thing to note is the conversion of initial responses into better responses over time in the cohort treated at the second dose level. Thus, it is still possible that the PRs with shorter follow-up in the highest dose cohort will continue to improve.

We can see some of the kinetics of response over time below:

The serum M-protein levels appear to continue to be trending down in the highest treated dose-cohort, so again, it is possible that the responses will continue to improve. The rapidity of the response appears to be roughly in line with what was seen previously in the NCI trial, but it's too few responses to really be able to have a good sense of this yet.

Bluebird also presented some initial CAR-T expansion and persistence data:

The CAR-T cells expanded for all dose cohorts, but appeared to expand to a greater extent for the two higher dose levels. The peak levels of the CAR-T cells - 10^5-10^6 vector copies per ug genomic DNA, appears to be similar to the peak expansion of 1.74 x 10^5 and 2.20 x 10^5 vc/ug genomic DNA in the two patients who had significant responses in the UPenn trial (table above). So it does not appear that the, as of yet, unobserved grade 3 or higher CRS is solely due to poor peak expansion of Bluebird's CAR-T cells.

The persistence also looks potentially improved versus the CD28 CAR in the NCI trial, which had minimal levels of CAR detectable by 3 months in any of their patients. While it is still very early in follow-up and patient numbers, Bluebird's 4-1BB CAR-T cells seem to maintain detectable levels in the majority of patients treated with the two highest doses through 8 weeks. Preliminary data from UPenn's 4-1BB BCMA CAR trial, as mentioned above, also had increased persistence, with CAR detectable for up to 7+ months in patients.

Decreases in serum BCMA levels correlated with response. For one patient with the longest follow-up in this figure (through 24 weeks), the CAR-T persistence appeared to wane by 8 weeks, and serum BCMA levels have begun to rise from 16-24 weeks, with re-emergence of CAR detection by 24 weeks. Further follow-up will be necessary to determine if this preludes a relapse.

Bluebird also presented a more detailed list of treatment emergent adverse events:

The grade 3 & higher toxicities were attributable to the lymphodepleting regimen. Again the headline has been the lack of observed grade 3 or higher CRS or neurotoxicity to date, even in patients who have had clinical responses.

They also gave additional details about the peak cytokine levels in their patients:

They show that their peak levels of cytokines in blood were all orders of magnitude below the very high levels observed in the NCI trial, in the two patients who had responses but also CRS (shown below). This is somewhat surprising that even with apparently significant CAR-T expansion they did not see very high levels of cytokines produced.

From Ali et al., 2016

Lastly, they said they plan on having a flexible trial design, potentially with different approaches for patients with higher disease burden versus low (using 50% bone marrow MM cells as a threshold). They also stated that patients enrolled so far were required to have BCMA detectable on >50% of their MM cells, but were considering loosening this criterion due to the impressive responses seen to date, hoping that their CAR will be able to detect even very low levels of antigen present on cells.

Summary

The data released by Bluebird on their still very early BCMA CAR-T program are certainly quite encouraging. They appear to compare favorably in terms of response rate to other early anti-BCMA CAR-T trials, although we are comparing small numbers here, and dose escalation in Bluebird's trial (and others) is still ongoing. More surprisingly, and impressively, unlike in previous trials, the activity of Bluebird's CAR-T cells has not been accompanied by grade 3 or higher CRS or neurotoxicity. One question that Bluebird has still not given further clarity on is what the disease burden was in these patients and we will have to see how disease burden will correlate with responses and toxicity going forward. The CAR-T cells did appear to expand significantly, but this has surprisingly not come with severe increases in cytokine levels and subsequent toxicity. These are definitely exciting results, but seeing how durable these responses are, as well as if these preliminary levels of activity and safety hold up with greater patient numbers will be of critical importance. As with CD19, loss of the target antigen, BCMA, will most likely be a difficulty going forward. If the safety and efficacy are, in fact, differentiated from other BCMA CAR-T programs, understanding why will be essential as well.



Disclosure: I own shares of Bluebird Bio