Amid the News on Allogenic CAR T Therapy, an Update on UCART19

There’s been plenty of buzz about allogenic or “off-the-shelf” chimeric antigen receptor (CAR) T-cell therapy at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida. But this is not the first ASH meeting to share news of the concept.

At last year’s gathering in San Diego, California, the French biotech Servier presented data on its universal anti-CD19 therapy, called UCART19.¹ The product made news amid reports that 82% of patients in pooled data from a pair of ongoing phase 1 studies (1 with adults, 1 with pediatric patients) who received a novel lymphodepletion regimen had achieved remission.¹ 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 that have been 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. Because the product is created from donor cells, the therapy features technology to deal with graft-versus-host disease (GVHD), notably a T-cell receptor (TCR) knockout that disrupts the TRAC gene.

Results reported this year at ASH show that healthy donor CAR T cells (n = 11) expanded significantly 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 diffuse large B-cell lymphoma (DLBCL) (n = 8).² Investigators said in their abstract that median CAR expression level was higher on for patients with CLL using the CAR T-cell product, compared with B-ALL patients and healthy donors. The TCR knockout caused the following:

• CD3 expression was lost on healthy donor TCR-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 were 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 those in patients with B-ALL.

The American Journal of Managed Care^® (AJMC^®) addressed questions about UCART19 to Patrick Therasse, MD, PhD, head of Research & Development Oncology, Servier Group. Under a licensing agreement with Pfizer, if the product is successfully developed and approved by FDA, it would be marketed in the United States through Allogene Therapuetics; Pfizer bought a 25% stake in Allogene in 2018.

AJMC^®: 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 modification, 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).

AJMC^®: 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 effector nuclease”. TALEN^® products are designed by fusing the DNA cutting domain of a nuclease to TALE domains, which can be tailored to specifically 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 modifications such as sequence insertion, deletion, repair and replacement in living cells.

AJMC^®: How does UCART19 stand apart from other allogenic treatments being presented during this year’s 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 first 21 patients were presented during ASH last year.¹ Today, 3 clinical trials are ongoing in pediatric and adult ALL, and non-Hodgkin’s lymphoma.

AJMC^®: 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 as compared to the autologous approach.

AJMC^®: 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 allogenic treatments to jump ahead of the current CAR-T offerings in the treatment guidelines?

Therasse: The use of CAR-T cell therapy earlier in the management of ALL patients has been discussed. One of the benefits 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 allogenic CAR Ts would behave differently than autologous CAR Ts in that setting.

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

Therasse: Improving the toxicity profile 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 differ between autologous and allogeneic CAR T-cells.

AJMC^®: What are the next research steps?

Therasse: Improving the efficacy while preserving the toxicity profile 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. Graham C, Jozwik A, Quartey-Papafio R, et al. Allogenic 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: The 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 3228. ash.confex.com/ash/2019/webprogram/Paper123018.html.