When it comes tochimeric antigen receptor (CAR) T-celltherapy, the waiting may hardest part for revolutionary, lifesaving treatment for certain leukemias and lymphomas. Manufacturing personalized treatments from apatients own cells can take up to 3 weeks, and payer approval canadd more time. The process itself is complicated and costlyatleast $373,000 before administration costsand reimbursementhas sometimes been slow.1
Thats why results highlighted December 7, 2019, at the 61stAmerican Society of Hematology (ASH) Annual Meeting &Exposition in Orlando, Florida, focused on the next wave of innovation,which features allogeneic, or off-the-shelf, treatmentsthat could offer greater convenience and lower costsand maketreatment available to more patients.
Gary Schiller, MD, of University of California, Los Angeles,Health, who moderated a press briefing on several abstractspresented at the meeting, said that advances in CAR T-cell therapyare overcoming multiple barriers:
Although first-generation therapies primarily target theprotein CD19, the next wave of treatment will attackmultiple targets. Therapies in the pipeline will treat more blood cancers,including multiple myeloma. A uniform product will replace the complex manufacturingprocess.
When we approach unmet needs in medicine, we solveone and we create another, saidStephen J. Schuster, MD, ofPenn Medicines Abramson Cancer Center in Philadelphia,Pennsylvania, who presented results on a novel therapy,mosunetuzumab. CAR T-cell therapy, Schuster said, has beena major advancehe led the JULIET trial in refractory B-celllymphomas that resulted in approval of the first therapy, Novartistisagenlecleucel (Kymriah).2 However, the two-thirds of patients that dont respond to CAR T-cell therapy are now our new unmetneed, he said.
Because patients eligible for CAR T are already quite ill, abouta third of those enrolled in clinical trials never make it to thepoint of getting therapy, ASH Secretary Robert A. Brodsky, MD,director of the Division of Hematology at Johns Hopkins School ofMedicine, said during a preview of the meeting.
Cost also poses a significant barrier to treatment.1,3 Academicmedical centers and Medicare have been locked in a struggleover how to pay for CAR T-cell therapy, because traditionalreimbursement designs were not created with this expensive,1-time treatment in mind.4 Although CMS announced in Augustthat 2020 would bring a modest increase in the new technologyadd-on payment, a November commentary in the Journal ofClinical Oncology pronounced that this quick fix does not go far enough.5 The authors estimated that hospitals lose $300,000 forevery patient treated with this technology.
Schuster presented results from a dosing study involvingmosunetuzumab, a bispecific antibody tested in 270 patientswith B-cell lymphomas that had returned or not responded toat least 3 therapies, including some patients who relapsed orfailed to respond to CAR T-cell therapy.6 The group included30 patients previously treated with CAR T-cell therapy. In a presspreview ahead of the 2019 meeting, ASH leaders speculated thatbispecific antibodies could supplant first-generation CAR T-cell treatments in some cancers if they can treat patients quicklyat a lower cost.
Unlike CAR T-cell therapy, mosunetuzumab does not requireindividualized genetic modification of a patients T cells. Instead,this therapy redirects T cells to engage and eliminate B cells,Schuster said. The new therapy produced durable responses in37% of the patients with aggressive non-Hodgkin lymphoma(NHL), a group that would benefit most from not having towait for individualized manufactured cells. Higher exposure tomosunetuzumab brought better responses, and a higher-dose study is now enrolling patients, Schuster said.
Across the studies presented at the meeting, patients generallyexperienced lower grades of cytokine release syndrome (CRS) thanseen in the first generation of CAR T-cell therapy. Hospitalizationdue to CRS has been a significant contributor to cost in the firstgeneration of CAR T-cell therapy; estimates of managing severecases range from $56,000 to more than $200,000.7
However, Schiller said, ease of access will likely be the top sellingpoint of these new therapies in the coming years. An off-the-shelfproduct is attractive because of feasibility issues, Schiller said.For patients previously treated with CAR T-cell therapy, it appearsthis new wave of treatments may salvage responses after a relapse,he said: It all depends on durability.
[For a] simple clinicianwho needs to take care of patientswith desperate diseases, tolerability is secondary to access andfeasibility, Schiller continued. So whatever productbe itcellular or bifunctionalthat we have access to tomorrow will bebetter and easier for us to use.
Abstracts presented at the briefing highlighted whatsin the pipeline:
MOSUNETUZUMAB. Schuster reported on complete remission (CR)in patients with relapsed/refractory NHL who were treated withthe study drug. In this phase 1/1b open-label study, accordingto the abstract, mosunetuzumab is given with step-up dosing ondays 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. Outcomesare best objective response rate (ORR), maximum tolerated dose(MTD), and tolerability.6
Results were the following:
The treatment produced promising responses in patientswith aggressive NHL. Among 124 patients (diffuse largeB-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 withindolent 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-celltherapy, 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, andthey have remained in remission, Schuster said. Some patientshave remained in remission without additional therapy formore than a year.
CAR NK PROOF-OF-CONCEPT. Bob Valamehr, PhD,of Fate Therapeutics, presented proof-of-conceptdata on an off-the-shelf cellular immunotherapythat targets 2 proteins on the surface of lymphomacells.8 The treatment, a targeted CAR natural killer(NK) cell, would be enhanced with features totake advantage of the properties of NK cellstheirability to attack and kill many types of cellswhileextending the cells durability. NK cells are multifacetedand can be viewed as a jack-of-all-trades whenit comes to protecting the host, whereas T cells canact in only 1 way, Valamehr said.
Fate Therapeutics developed a master line of NKcells induced from specialized stem cells (iNK cells),known as FT596, which overcomes a challenge of CAR T therapy: lack of uniformity that can occurwith individualized products. When you [manufacture]the product, not every cell is engineered, andnot every engineered cell is pristine, Valamehr said.
According to the abstract,8 FT596 cells aredesigned to carry 3 genes at once:
An NK cell-calibrated CAR that targets CD19 Noncleavable CD16, which enhancesbinding activity A recombinant fusion of interleukin (IL) 15and IL-15 receptor- (IL-R) that extendspersistence of the cells
Investigators did experiments in both in vitroand in mouse models and found that iNK cellsengineered with both CD19-CAR and IL-R werecurative against B-cell lymphoma comparedwith iNK cells either alone or modified only withCD19-CAR. The investigators next performed testsusing various combinations with rituximab andreported that only FT596 was able to effectivelyeliminate the CD19 antigen escaped target cell.7
According to the abstract, experiments usingthe allogeneic therapy on a mouse model showedthat FT596 demonstrated improved survivaland safety over primary CAR19 T cells, whetherused as alone or in combination with rituximab.Experiments with rituximab showed great potentialfor that combination.
If successful, this approach could be administeredmuch like traditional therapies, according toValamehr. The process creates a homogeneous,high-quality product thats low cost, he said.Each dose is $2500. Its directly infused; there is noprocessing needed, so it becomes a true, administeredoff-the-shelf product in an outpatient setting.
MULTIPLE MYELOMA. The session also covered apair 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 atherapy containing 2 proteins designed to targetthe B-cell maturation antigen. Deepu Madduri,MD, of Mount Sinai in New York, New York, sharedthe news that the FDA granted JNJ-4528 breakthroughtherapy designation on the eve of the ASH meetingDecember 6, 2019.11
We know that there have been a lot of advancesover the last few years [in] multiple myeloma,Madduri said, and so people are living longer.However, for patients who have failed all availabletherapies, median overall survival is less than12 months, he said.
This study involved 29 patients, 25 of whom had atleast 3 prior therapies, including autologous transplantation.The investigators said the results showthat JNJ-4528 at a dose of 0.75 x 106 CAR-positivecells/kg brings an early and deep response, featuringminimal residual disease negativity in all evaluablepatients tested.9
Of note: Not only were CRS events of lower gradethan in first-generation CAR T therapies, butthe median time of onset was 7 days, >90%between 5 and 9 days, later than in the past. Neurotoxicity was infrequently observed andgenerally low grade. Early and deep responses were seen: 100%ORR, with CR 69% at 6 months. The median time to first response was 1month, as was the median time to CR; 27 of 29patients were progression free at 6 months.
1. Andrews M. Staggering price slow insurers coverage of CAR-T cancertherapy. 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. Tisagenlecleucelin 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 Europeanmeeting. 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 atthe mercy of payment policy: the future of chimeric antigen receptortherapies [published online November 1, 2019]. J Clin Oncol.doi: 10.1200/JCO.19.01691.
6. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab inducescomplete remissions in poor prognosis non-Hodgkin lymphomapatients, including those who are resistant to or relapsing after chimericantigen receptor T-cell (CAR-T) therapies, and is active in treatmentthrough multiple lines. Presented at: 61st American Society of HematologyMeeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 6.ash.confex.com/ash/2019/webprogram/Paper123742.html.
7. Mulcahy N. Whats the total cost of one CAR T-cell treatment? Medscapewebsite. 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-kindmulti-antigen targeted off-the-shelf CAR-NK cell with engineeredpersistence for the treatment of B-cell malignancies. Presented at:61st American Society of Hematology Meeting & Exposition; December7-10, 2019; Orland, FL. Abstract 301. ash.confex.com/ash/2019/webprogram/Paper129319.html.
9. Madduri D, Usmani SZ, Janannath S. Results from CARTITUDE-1: aphase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed againstB-cell maturation antigen (BCMA), in patients with relapsed and/orrefractory multiple myeloma (R/R MM). Poster and abstract presentedat: 61st American Society of Hematology Meeting & Exposition; December7-10, 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 CART-targeting B cell maturation antigen in relapsed/refractory multiplemyeloma. 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 multiplemyeloma. 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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CAR T-Cell Therapy and Beyond: Off-the-Shelf Therapies Among Innovations at ASH 2019 - AJMC.com Managed Markets Network
