CAR T-Cell Therapy and Beyond: Off-the-Shelf Therapies Among Innovations at ASH 2019

When it comes to chimeric antigen receptor (CAR) T-cell therapy, the waiting may hardest part for revolutionary, lifesaving treatment for certain leukemias and lymphomas. Manufacturing personalized treatments from a patient’s own cells can take up to 3 weeks, and payer approval can add more time. The process itself is complicated and costly—at least $373,000 before administration costs—and reimbursement has sometimes been slow.¹

That’s why results highlighted December 7, 2019, at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida, focused on the next wave of innovation, which features allogeneic, or “off-the-shelf,” treatments that could offer greater convenience and lower costs—and make treatment available to more patients.

Gary Schiller, MD, of University of California, Los Angeles, Health, who moderated a press briefing on several abstracts presented at the meeting, said that advances in CAR T-cell therapy are overcoming multiple barriers:

• Although first-generation therapies primarily target the protein CD19, the next wave of treatment will attack multiple targets.

• Therapies in the pipeline will treat more blood cancers, including multiple myeloma.

• A uniform product will replace the complex manufacturing process.

“When we approach unmet needs in medicine, we solve one and we create another,” said Stephen J. Schuster, MD, of Penn Medicine’s Abramson Cancer Center in Philadelphia, Pennsylvania, who presented results on a novel therapy, mosunetuzumab. CAR T-cell therapy, Schuster said, has been a major advance—he led the JULIET trial in refractory B-cell lymphomas that resulted in approval of the first therapy, Novartis’ tisagenlecleucel (Kymriah).² “However, the two-thirds of patients that don’t respond to CAR T-cell therapy are now our new unmet need,” he said.

Because patients eligible for CAR T are already quite ill, about a third of those enrolled in clinical trials never make it to the point of getting therapy, ASH Secretary Robert A. Brodsky, MD, director of the Division of Hematology at Johns Hopkins School of Medicine, said during a preview of the meeting.

Cost also poses a significant barrier to treatment.^1,3 Academic medical centers and Medicare have been locked in a struggle over how to pay for CAR T-cell therapy, because traditional reimbursement designs were not created with this expensive, 1-time treatment in mind.⁴ Although CMS announced in August that 2020 would bring a modest increase in the new technology add-on payment, a November commentary in the Journal of Clinical Oncology pronounced that “this quick fix does not go far enough.”⁵ The authors estimated that hospitals lose $300,000 for every patient treated with this technology.

Schuster presented results from a dosing study involving mosunetuzumab, a bispecific antibody tested in 270 patients with B-cell lymphomas that had returned or not responded to at least 3 therapies, including some patients who relapsed or failed to respond to CAR T-cell therapy.⁶ The group included 30 patients previously treated with CAR T-cell therapy. In a press preview ahead of the 2019 meeting, ASH leaders speculated that bispecific antibodies could supplant first-generation CAR T-cell treatments in some cancers if they can treat patients quickly at a lower cost.

Unlike CAR T-cell therapy, mosunetuzumab does not require individualized genetic modification of a patient’s T cells. Instead, this therapy redirects T cells to engage and eliminate B cells, Schuster said. The new therapy produced durable responses in 37% of the patients with aggressive non-Hodgkin lymphoma (NHL), a group that would benefit most from not having to wait for individualized manufactured cells. Higher exposure to mosunetuzumab brought better responses, and a higher-dose study is now enrolling patients, Schuster said.

Across the studies presented at the meeting, patients generally experienced lower grades of cytokine release syndrome (CRS) than seen in the first generation of CAR T-cell therapy. Hospitalization due to CRS has been a significant contributor to cost in the first generation of CAR T-cell therapy; estimates of managing severe cases range from $56,000 to more than $200,000.⁷

However, Schiller said, ease of access will likely be the top selling point of these new therapies in the coming years. “An off-the-shelf product is attractive because of feasibility issues,” Schiller said. For patients previously treated with CAR T-cell therapy, it appears this new wave of treatments may salvage responses after a relapse,

he said: “It all depends on durability.

“[For a] simple clinician…who needs to take care of patients with desperate diseases, tolerability is secondary to access and feasibility,” Schiller continued. “So whatever product—be it cellular or bifunctional—that we have access to tomorrow will be better and easier for us to use.”

Abstracts presented at the briefing highlighted what’s in the pipeline:

MOSUNETUZUMAB. Schuster reported on complete remission (CR) in patients with relapsed/refractory NHL who were treated with the study drug. In this phase 1/1b open-label study, according to the abstract, mosunetuzumab is given with step-up dosing on days 1, 8, and 15 of cycle 1, then as a fixed-dose on day 1 of each subsequent 21-day cycle, for a maximum of 17 cycles. Outcomes are best objective response rate (ORR), maximum tolerated dose (MTD), and tolerability.⁶

Results were the following:

• The treatment produced promising responses in patients with aggressive NHL. Among 124 patients (diffuse large B-cell lymphoma, follicular lymphoma), ORR was 37.1% (46 patients) and CR was 19.4% (24 patients) (FIGURE).

• As expected, responses were better for patients with indolent NHL. Among the 67 patients, ORR was 62.7% (42 patients), and 29 (43.3%) had a CR.

• Among the first 18 patients with prior CAR T-cell therapy, ORR was 38.9% (7 patients), and 4 patients (22.2%) had a CR.

• Four patients were able to be retreated with mosunetuzumab; among these, 3 (75%) had an ORR, and 1 had a CR.

“I have stopped therapy in some patients after 6 months, and they have remained in remission,” Schuster said. “Some patients have remained in remission without additional therapy for more than a year.”

CAR NK PROOF-OF-CONCEPT.

Bob Valamehr, PhD, of Fate Therapeutics, presented proof-of-concept data on an off-the-shelf cellular immunotherapy that targets 2 proteins on the surface of lymphoma cells.⁸ The treatment, a targeted CAR natural killer (NK) cell, would be enhanced with features to take advantage of the properties of NK cells—their ability to attack and kill many types of cells—while extending the cells’ durability. “NK cells are multifaceted and can be viewed as a jack-of-all-trades when it comes to protecting the host, whereas T cells can act in only 1 way,” Valamehr said.

Fate Therapeutics developed a master line of NK cells induced from specialized stem cells (iNK cells), known as FT596, which overcomes a challenge of CAR T therapy: lack of uniformity that can occur with individualized products. “When you [manufacture] the product, not every cell is engineered, and not every engineered cell is pristine,” Valamehr said.

According to the abstract,8 FT596 cells are designed to carry 3 genes at once:

• An NK cell-calibrated CAR that targets CD19 • Noncleavable CD16, which enhances binding activity

• A recombinant fusion of interleukin (IL) 15 and IL-15 receptor-α (IL-Rα) that extends persistence of the cells

Investigators did experiments in both in vitro and in mouse models and found that iNK cells engineered with both CD19-CAR and IL-Rα “were curative against B-cell lymphoma” compared with iNK cells either alone or modified only with CD19-CAR. The investigators next performed tests using various combinations with rituximab and reported that “only FT596 was able to effectively eliminate the CD19 antigen escaped target cell.”⁷

According to the abstract, experiments using the allogeneic therapy on a mouse model showed that FT596 “demonstrated improved survival and safety over primary CAR19 T cells,” whether used as alone or in combination with rituximab. Experiments with rituximab showed great potential for that combination.

If successful, this approach could be administered much like traditional therapies, according to Valamehr. The process creates “a homogeneous, high-quality product that’s low cost,” he said. “Each dose is $2500. It’s directly infused; there is no processing needed, so it becomes a true, administered off-the-shelf product in an outpatient setting.”

MULTIPLE MYELOMA.

The session also covered a pair of CAR T-cell therapies for multiple myeloma, taking advantage of the dual target approach. Results from CARTITUDE-1,⁹ funded by Janssen, confirm results from the LEGEND-2 study¹⁰ for a therapy containing 2 proteins designed to target the B-cell maturation antigen. Deepu Madduri, MD, of Mount Sinai in New York, New York, shared the news that the FDA granted JNJ-4528 breakthrough therapy designation on the eve of the ASH meeting—December 6, 2019.¹¹

“We know that there have been a lot of advances over the last few years [in] multiple myeloma,” Madduri said, “and so people are living longer.” However, for patients who have failed all available therapies, “median overall survival is less than 12 months,” he said.

This study involved 29 patients, 25 of whom had at least 3 prior therapies, including autologous transplantation. The investigators said the results show that JNJ-4528 at a dose of 0.75 x 106 CAR-positive cells/kg brings an early and deep response, featuring minimal residual disease negativity “in all evaluable patients tested.”⁹

Of note:

• Not only were CRS events of lower grade than in first-generation CAR T therapies, but the median time of onset was 7 days, >90% between 5 and 9 days, later than in the past.

• Neurotoxicity was infrequently observed and generally low grade.

• Early and deep responses were seen: 100% ORR, with ≥CR 69% at 6 months.

• The median time to first response was 1 month, as was the median time to ≥CR; 27 of 29 patients were progression free at 6 months. References

1. Andrews M. Staggering price slow insurers’ coverage of CAR-T cancer therapy. Kaiser Health News. khn.org/news/staggering-prices-slow-insurers-coverage-of-car-t-cancer-therapy/. Published July 17, 2018. Accessed December 10, 2019.

2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi: 10.1056/NEJMoa1804980.

3. Worcester S. Barriers to CAR T use in the spotlight at first European meeting. MDedge website. mdedge.com/hematology-oncology/article/195404/immuno-oncology/barriers-car-t-use-spotlight-first-european. Published February 28, 2019. Accessed December 10, 2019.

4. Caffrey M. NCCN panel digs into reality of CAR T-cell reimbursement. The American Journal of Managed Care® website. ajmc.com/conferences/nccn-2019/nccn-panel-digs-into-reality-of-car-tcell-reimbursement. Published March 21, 2019. Accessed December 10, 2019.

5. Manz CR, Porter DL, Bekelman JE, et al. Innovation and access at the mercy of payment policy: the future of chimeric antigen receptor therapies [published online November 1, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.01691.

6. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. Presented at: 61st American Society of Hematology Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 6. ash.confex.com/ash/2019/webprogram/Paper123742.html.

7. Mulcahy N. What’s the total cost of one CAR T-cell treatment? Medscape website. medscape.com/viewarticle/895735. Published April 26, 2018. Accessed December 7, 2019.

8. Goodridge JP, Mahnood S, Zhu H, et al. Translation of first-of-kind multi-antigen targeted off-the-shelf CAR-NK cell with engineered persistence for the treatment of B-cell malignancies. Presented at: 61st American Society of Hematology Meeting & Exposition; December 7-10, 2019; Orland, FL. Abstract 301. ash.confex.com/ash/2019/webprogram/Paper129319.html.

9. Madduri D, Usmani SZ, Janannath S. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Poster and abstract presented at: 61st American Society of Hematology Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 577. ash.confex.com/ash/2019/webprogram/Paper121731.html.

10. Xu J, Chen LJ, Yang SS, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A. 2019;116(19):9543-9551. doi:10.1073/pnas.1819745116.

11. House D. J&J CAR T nabs accelerated review status in US for multiple myeloma. Seeking Alpha website. seekingalpha.com/news/3524575-jand-j-car-t-nabs-accelerated-review-status-in-u-s-for-multiple-myeloma. Published and accessed December 6, 2019.

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