Persistence of CAR T Cells Seen in "Next-Generation" Anti-BCMA Therapy, bluebird bio's Ide-cel

Although results for Janssen’s investigational chimeric antigen receptor (CAR) T-cell therapy directed against B-cell maturation antigen (BCMA) appeared on the press program at the 61st American Society of Hematology (ASH) in Orlando, Florida,¹ analysts were equally impressed² with results for a competing anti-BCMA from bluebird bio and Bristol-Myers Squibb.³

The company presented updated phase 1 results³ for a revamped version of bb2121 that point to sustained responses for patients with relapsed/refractory multiple myeloma (RRMM). Both versions are built on the idecabtagene vicleucel (ide-cel; bb2121). Separately, bluebird bio and Bristol-Myers Squibb also announced positive topline results for a phase 2 pivotal trial called KarMMa.⁴

The updated phase 1 dose escalation trial (CRB-402) is a first-in-human study of bb21217, so called because ide-cel is enhanced with the phosphoinositide 3-kinase inhibitor bb007 to create “memory-like” T cells. As of September 4, 2019, the study included data for 38 patients with a median of 6 prior lines of therapy; 82% had at least 1 autologous stem cell transplant:

• 24 patients received the therapy at 3 dose levels: 12 at 150 x 10⁶ CAR+ T cells; 6 at 300 x 10⁶ CAR+ T cells; and 6 at 450 x 10⁶ CAR+ T cells.
• 14 patients received therapy in the dose expansion cohort at 2 dose levels: 8 at 300 x 10⁶ CAR+ T cells and 6 at 450 x 10⁶ CAR+ T cells.

The American Journal of Managed Care^® (AJMC^®) discussed the results and CAR T-cell therapy for multiple myeloma with bluebird bio’s Liviu Niculescu, MD, PhD, senior vice president for global medical affairs.

AJMC^®: We’ve been hearing about CAR T-cell therapy in multiple myeloma for a while. What are the challenges of using a CAR T-cell approach for this particular blood cancer?

Niculescu: The fundamental challenge associated with the treatment of multiple myeloma is the relentlessness of the disease. Treatment outcomes have decidedly improved for myeloma patients over the last decade, which is reflective of the introduction and availability of many new effective treatment options. However, the disease remains incurable with the majority of patients experiencing relapse, at which time the patient’s disease becomes more and more difficult to treat.

CAR T therapies are shown to provide relapsed and refractory myeloma patients with durable remissions after a single administration, allowing these patients additional time to live without their disease getting worse. However, many of these patients relapse and require further treatment. Understanding the underlying mechanism of relapse after CAR T therapy is a key challenge today. When we begin to understand this incredibly complex question, we can further explore ways to improve CAR T therapies. This question of how to improve CAR T therapy in order to increase outcomes for patients is what led to the development of bb21217.

These therapies are promising and at the forefront of innovative science, but there are also practical challenges. Many patients with multiple myeloma are treated in community practice settings and CAR T therapy is only administered in specialized centers. So, finding the right treatment centers and providing a smooth experience for the patient is a key focus as we potentially bring CAR T therapy to patients with multiple myeloma.

AJMC^®: BCMA-based immunotherapies for multiple myeloma have received lots of attention. Can you discuss the value of this approach [bb21217] generally and how bluebird bio’s concept of enriching T cells to improve “memory” improves persistence?

Niculescu: bb21217 is an investigational BCMA-targeted CAR T cell therapy that uses the idecabtagene vicleucel (ide-cel; bb2121) CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention to increase the in vivo persistence of CAR T cells. Evidence suggests that memory like T cells may persist in patients for a longer time than other types of T cells, and it is hypothesized that the persistent memory like CAR T cells may be important for increasing durability of response.

As of September 4, 2019, CAR T cell persistence in CRB-402 was observed in 8 of 10 patients with ongoing response and evaluable at six months, and 2 out of 2 patients with ongoing response and evaluable at 18 months. Initial data, based on limited follow-up, suggest that enrichment for memory-like CAR T cells in bb21217 drug product was associated with both increased peak CAR T expansion and achievement of sustained clinical response at 6 months.

Longer follow-up is needed to define any association with long-term persistence and response. It is important to note that these are early data and analyses of long-term CAR T-cell persistence require additional follow-up. We continue to assess the functional persistence of bb21217 in this ongoing study, as well as its potential correlation with durability of response.

AJMC^®: Toxicity has been an issue with the first generation of CAR T-cell therapy, although this seems to be improving with the next generation of treatments. How does bb21217 compare in toxicity relative to both the first generation of CAR T and some of the newer treatments on the horizon?

Niculescu: As of September 4, 2019, the safety profile of bb21217 is consistent with known toxicities of CAR T therapies, regardless of dose level. As we continue gain more experience with CAR T therapies and conduct additional research, physicians have become more comfortable with managing common adverse events (AE) like cytokine release syndrome and neurotoxicity. AE management guidelines have been developed and we can see improvements in the prevention and treatment of these AEs.

AJMC^®: Can you discuss the effectiveness of bb21217 in helping patients achieve undetectable minimal residual disease (MRD)?

Niculescu: As of September 4, 2019, evidence of myeloma in the bone marrow, known as minimal residual disease (MRD), was undetectable by next-generation sequencing at a sensitivity level of 10^-5 in 94% (n=16/17) of all confirmed responders who had evaluable bone marrow samples (patients with ≥ PR and ≥ 1 valid post-baseline MRD assessment).

AJMC^®: As multiple myeloma is a very heterogeneous disease, which patients would benefit most from bb21217?

Niculescu: We are investigating bb21217 in a group of heavily pretreated multiple myeloma patients who have been exposed to most mechanisms of action currently available to treat the disease (anti-CD38, proteasome inhibitors and immunomodulators). These patients are now refractory to their treatment, meaning that their disease is progressing during treatment, or within 60 days after, so they have very limited additional options.

We can’t comment on the market use of an investigational therapy, but it is important to note that multiple myeloma is a relentless disease and there is significant need to find new treatment options for patients who advance through the current therapies available to them.

The current data support ongoing investigation to fully understand the potential role of bb21217 in the multiple myeloma treatment paradigm. We continue to enroll patients at the recommended phase 2 dose in order to further evaluate the efficacy of bb21217 and we look forward to sharing updated data as it matures.

References

1. New approaches aim to enhance CAR T-cell therapy [press release]. Orlando, FL: American Society of Hematology; December 7, 2019. hematology.org/Newsroom/Press-Releases/2019/10096.aspx Accessed December 7, 2019.
2. Lee J. Investors shift attention to next generation of CAR T, new sickle cell treatments at major hematology meeting. MarketWatch website. marketwatch.com/story/investors-shift-attention-to-next-generation-of-car-t-new-sickle-cell-treatments-at-major-hematology-meeting-2019-12-10. Published December 12, 2019. Accessed December 17, 2019.
3. Berdeja JG, Alsina M, Shah ND, et al. Updated results from an ongoing phase I clinical study of bb21217 anti-BCMA CAR T-cell therapy. Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 927. ash.confex.com/ash/2019/webprogram/Paper126660.html.
4. Bristol-Myers Squibb and bluebird bio announce positive top-line results from the pivotal phase 2 KarMMa study of Ide-cel in relapsed and refractory multiple myeloma [press release]. Princeton, NJ, and Cambridge, MA: Bristol-Myers Squibb; December 6, 2019. news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-announce-positive-top-li. Accessed December 17, 2019.