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CAR T-Cell Therapy and Beyond: UCART 19 and Anti-BCMA Therapy

Publication
Article
Evidence-Based OncologyJanuary 2020
Volume 26
Issue 1

A pair of interviews on investigational therapies whose sponsors reported updates at the 61st American Society of Hematology Annual Meeting and Exposition: UCART19 from Servier and a revamped anti-BCMA therapy ide-cel from bluebird bio.

Update on UCART19 Arrives Amid News on Allogeneic CAR T Therapy

Despite all the buzz about allogeneic or “off -the-shelf” chimeric antigen receptor (CAR) T-cell therapy at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida, the concept was not new to ASH meetings.

At the 2018 gathering in San Diego, California, the French biotech Servier presented data on its universal anti-CD19 therapy, UCART19.1 The product made news amid reports that“in pooled data from a pair of ongoing phase 1 studies (1 with adults, 1 with pediatric patients), 82% of patients who received a novel lymphodepletion regimen had achieved remission.2 “This is done by knocking out the CD52 gene, allowing the therapy alemtuzumab to be used in this process.

UCART19 is manufactured from healthy donor T cells and features a safety switch, the CD20 mimotope RQR8, that lets rituximab bind to the CAR T cells. This halts the runaway responses associated with CAR T treatment, dramatically reducing adverse events such as cytokine response syndrome. This mechanism was initially developed by Servier’s collaborator,“Cellectis,“which exclusively licensed UCART19 to Servier.3 Because the product is created from donor cells, the therapy features technology to deal with graft-vs-host disease—notably, a T-cell receptor (TCR) knockout that disrupts the “TRAC" gene.

Results reported at the 2019 ASH meeting show that healthy donor CAR T cells (n = 11) expanded signifi cantly during the manufacturing process compared with those derived from B-cell acute lymphoblastic leukemia (B-ALL; n = 9), chronic lymphocytic leukemia (CLL; n = 8), or diff use large B-cell lymphoma (DLBCL; n = 8).4 Investigators said in their abstract that median CAR expression level was higher for patients with CLL using the CAR T-cell product compared with B-ALL patients and healthy donors.

The TCR knockout led to the following results:

• CD3 expression was lost on healthy donor TCR-negative CAR T cells, except for a distinct population called γδ CAR T cells.

• CLL and DLBCL CD8-CAR cells expressed higher levels of PD-1 than healthy donor CD8- CAR T cells.

• In 2018, CAR-CD8-CD27-PD-1 T cells we re described as “functionally important” and correlated with clinical outcomes in patients who got the CLL CAR T cells.

• Healthy donor and healthy donor TCR CAR T cells had more CD8, CD27, and PD-1 CAR T cells compared with those derived from CLL and DLBCL but similar to the amount of those in patients with B-ALL.

Evidence-Based Oncology™ (EBO) posed questions about UCART19 to Patrick Therasse, MD, PhD, head of Research & Development, Oncology, at Servier Group. Under a“licensing agreement with Pfizer, if successfully developed and then approved by the FDA, the product would be marketed in the United States through Allogene Therapeutics. Pfi zer bought a 25% stake in Allogene in 2018.

EBO:

The approach of UCART19 appears to strike a balance: You use healthier cells to overcome weaknesses that develop due to prior treatments and cancer itself, while guarding against the potential for rejection through modifi cation, via knockouts of TRAC and CD52. Is this the basic concept? What are the advantages and disadvantages compared with the current approach to CAR T-cell treatment?

THERASSE:

Yes, this is basically the approach: overcoming the limitations associated with the use of autologous CAR T approaches including lengthy vein-to-vein time, manufacturing failure, variable potency, and high production cost. We believe that the use of innovative technology to modify nonmatched allogeneic healthy donor T cells may allow the treatment of a broad patient population with a product of consistent quality standards. If UCART19 is approved, the treatment could begin soon after diagnosis, which could be vital in a fast-progressing disease such as acute lymphoblastic leukemia [ALL].

EBO:

UCART19 uses trademarked technology called TALEN. What does TALEN stand for, and can you discuss the basic mechanism?

THERASSE:

TALEN“is a gene-editing technology pioneered and owned by our partner Cellectis. It stands for “transcription activator-like eff ector nuclease.” TALEN products are designed by fusing the DNA cutting domain of a nuclease to TALE domains, which can be tailored to specifi cally recognize a unique DNA sequence.

These fusion proteins serve as readily targetable “DNA scissors” for gene-editing applications that enable us to perform targeted genome modifi cations such as sequence insertion, deletion, repair, and replacement in living cells.

EBO:

How does UCART19 stand apart from other allogeneic treatments presented at the 2019 meeting?

THERASSE: UCART19 is the most advanced allogeneic CAR T product in clinical development. It entered clinical development in 2016, and encouraging clinical data from the fi rst 21 patients were presented during ASH [in 2018].1 “Today, 3 clinical trials are ongoing in pediatric and adult ALL and non-Hodgkin lymphoma.

EBO: Will this approach be less costly than current CAR T-cell treatments—not just in the therapy itself but also in administrative/hospitalization costs? Have estimates been developed? If so, what are the potential benefits to payers, especially Medicare?

THERASSE:

Cost is clearly a key parameter with regard to CAR Ts. By using the allogeneic approach, we hope to be able to treat 10 to 100 patients from a single manufacturing run. This will certainly allow to decrease the cost of treatment compared with the autologous approach.

EBO:

There have already been discussions that CAR T-cell therapy should be given earlier, before cells are depleted by prior treatments. Is there potential for allogeneic treatments to jump ahead of the current CAR-T offerings in the treatment guidelines?

THERASSE: Using CAR-T cell therapy earlier in the management of ALL patients has been discussed. One of the benefi ts could be to avoid the long-term toxicity that may be associated with the use of chemotherapies, especially in pediatric patients. It is too early to tell if allogeneic CAR Ts would behave diff erently than autologous

CAR Ts in that setting.

EBO:

Is it possible yet to say what the difference would be in toxicity compared with current CAR T treatments?

THERASSE:

Improving the toxicity profi le of CAR T-cell therapies is also one of our objectives when developing next-generation allogeneic CAR Ts. It is too early today to make any conclusion, but preliminary data suggest that toxicity may diff er between autologous and allogeneic CAR T-cells.

EBO:

What are the next research steps?

THERASSE:

Improving the efficacy while preserving the toxicity profi le of CAR Ts, together with optimizing the manufacturing process, are our main objectives today. For the future, challenges will be to extend CAR T-cell therapies to other targets and indications, including solid tumors.

References

1. Benjamim R, Graham C, Yallop D, et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia. Blood.†2018;132(suppl 1):896. doi: 10.1182/blood-2018-99-111356.

2. Servier and Allogene Therapeutics present pooled data from phase 1 trials of allogeneic UCART19 in relapsed/refractory acute lymphoblastic leukemia [press release]. Paris, France, and South San Francisco, CA: Servier; December 4, 2018. servier.com/en/communique/servier-and-allogene-therapeutics-present-pooled-data-from-phase-1-trials-of-allogeneic-ucart19-in-relapsed-refractory-acute-lymphoblastic-leukemia/. Accessed December 9, 2019.

3. Cellectis and Servier announce collaboration in allogeneic cell therapy: UCART19 to treat leukemia and 5 product candidates targeting solid tumors [press release]. Paris, France: Cellectis website; February 17, 2014. cellectis.com/en/press/cellectis-and-servier-announce-collaboration-in-allogeneic-cell-therapy-ucart19-to-treat-leukemia-and-5-product-candidates-targeting-solid-tumors. Accessed December 10, 2019.

4. Graham C, Jozwik A, Quartey-Papafio R, et al. Allogeneic anti-CD19 CAR T cells manufactured from healthy donors provide a unique cellular product with distinct phenotype characteristics compared to CAR T cells generated from patients with mature B cell malignancies. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 3228. ash.confex.com/ash/2019/webprogram/Paper123018.html.

5. Pfizer hands UCART19, allogenic CAR-T portfolio rights to $300M startup. Genetic Engineering & Biotechnology News website. genengnews.com/topics/drug-discovery/pfizer-hands-ucart19-allogenic-car-t-portfolio-rights-to-300m-startup/. Published April 3, 2018. Accessed December 10, 2019.

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.

Evidence-Based Oncology™ (EBO) 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.

EBO: 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 refl ective of the introduction and availability of many new eff ective 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.

EBO:

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 Tcell 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 defi ne 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.

EBO:

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 profi e 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.

EBO: Can you discuss the eff ectiveness 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 confi rmed responders who had evaluable bone marrow samples (patients with ≥PR and ≥1 valid post-baseline MRD assessment).

EBO:

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 fi nd 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-nextgeneration-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-andbluebird-bio-announce-positive-top-li. Accessed December 17, 2019.

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