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Pivotal Year Looms for CAR T-Cell Therapies

Chimeric antigen receptor T-cell therapies have already produced clinical trial results that, even by the lofty standards set by emerging immunotherapies, have been stunning.

Steven A. Rosenberg, MD, PhD

Chimeric antigen receptor (CAR) T-cell therapies have already produced clinical trial results that—even by the lofty standards set by emerging immunotherapies—have been stunning. This year should demonstrate whether the most tested treatments in the class perform as well in real-world patients and whether new agents can produce similarly spectacular trial results against a wider variety of cancers.

Kite Pharma has initiated a rolling submission with the FDA for permission to market KTE-C19 (axicabtagene ciloleucel) for use in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.1 The new drug application will rest largely on the strength of the ZUMA-1 trial, which produced an objective response rate (ORR) of 91% and a complete remission (CR) rate of 73%.2

Novartis, meanwhile, plans to seek FDA approval early this year to market CTL019 (tisagenlecleucel- T) to pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).3 That application will hinge on the positive results of the phase II ELIANA trial, which, according to an oral presentation at the 2016 American Society of Hematology (ASH) Annual Meeting, produced a CR or a CR with incomplete blood count recovery (CRi) in 82% (41 of 50) patients with B-cell ALL.

The FDA awarded breakthrough therapy designations to both medications on grounds that they address unmet needs.4 The agency also is evaluating two CAR T-cell therapies from Juno Therapeutics, JCAR017 and JCAR015, through the breakthrough therapy program, which is aimed at prioritizing reviews of promising drugs.4

Development plans for JCAR015 in adult patients with relapsed/refractor B-cell ALL have been in flux since November 2016 when Juno Therapeutics voluntarily placed the phase II ROCKET trial on hold after 2 patients, like 3 other participants before them, died from cerebral edema.5 The hold does not affect the company’s efforts to develop JCAR017 or other CAR T-cell therapies.

Other companies seeking to bring CAR therapies to market include:

• Bluebird Bio is working with Celgene to conduct a phase I trial of its lead CAR T candidate, bb2121, in patients with relapsed and refractory multiple myeloma.6 It also reports several other T-cell receptor (TCR) adoptive immunotherapy candidates in preclinical stages of development.7

• Cellectis has begun phase I trials of its lead therapy, UCART19, in patients with ALL and chronic lymphocytic leukemia (CLL)8 and has asked the FDA for permission to launch phase I trials of UCART123 in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm.9

Scope of New Therapies

• Adaptimmune and partner GlaxoSmithKline are conducting early-stage trials of NY-ESO TCR in patients with synovial sarcoma, multiple myeloma, melanoma, ovarian cancer and non— small cell lung cancer (NSCLC). The company has also launched a phase I trial of MAGE-A10 TCR in NSCLC and is about to begin testing the treatment against melanoma as well as cancers of the bladder, head and neck.10If these novel CAR therapies prove successful, the treatments could provide extra years of life for real-world patients. That would be great news for patients, particularly those with recurrent and incurable hematological cancers, which are the current focus of most companies.

“There is definitely reason for optimism that CAR-T treatments will prove effective against a wide range of hematological cancers. There are a number of B-cell malignancies that express the CD19 antigen that it targeted in most of the treatments that have done so well in trials to date, and we’re starting to see some evidence that CAR-T therapies with alternate targets or alternate vectors may work against a number of CD19- negative malignancies,” said Charles Mullighan, MD, chairman of ASH’s Committee on Scientific Affairs.

“Of course, it will be several years until we know for sure how big an impact CAR-T will have on hematology as a whole, but we are already seeing this as a major new weapon in our arsenal against relapsed or refractory ALL,” he said. Meanwhile, efforts to engineer CAR T-cell therapies for use against solid tumors continue. New targets for CAR therapies in solid tumors and a greater understanding of the differences in their activity compared with hematologic malignancies is needed, researchers have said.11

In an article in Cell Research, gene engineering pioneer Carl H. June, MD, a Giants of Cancer Care® award winner, and colleague Laura A. Johnson, PhD, both of the University of Pennsylvania’s Perelman School of Medicine, noted that the discovery that tumor-infiltrating lymphocytes could be expanded and used to treat metastatic melanoma helps set the stage for the use of adoptive cell therapy in solid tumors.11

Although there has been a lack of success with CARs in solid tumors thus far, there also have been few completed clinical trials with published data, the authors said.11

Steven A. Rosenberg, MD, PhD, a groundbreaking immunotherapy researcher who has helped develop the new generation of CARs, also acknowledged the success of CAR therapies thus far and the knowledge gap that must be overcome to extend their use into solid tumors.

“CAR T-cell therapies have produced very impressive results in a number of trials. I believe they will be able to extend the life and possibly cure relapsed or refractory lymphoma and leukemia patients whose cancers can be targeted by CARs,” said Rosenberg, chief of the National Cancer Institute’s Surgery Branch, who also has been named a Giants of Cancer Care® award winner.

“Unfortunately, it appears at this point that CAR T cells will not work against the vast majority of solid tumor types that together account for the vast majority of cancer deaths. CAR T-cell therapy is a revolutionary treatment, but only for a relatively small number of people. I believe an important part of the future of cell transfer therapy for cancer will involve natural T cells reactive with mutations expressed by the cancer,” said Rosenberg.

The idea of grafting CARs onto T cells drawn from individual patients so that those T cells would attack particular diseases with those particular antigens dates back more than 3 decades. A team led by Zelig Eshhar, PhD, an immunologist from the Weizmann Institute of Science, produced the first functional CAR T cells in 1989,12 but early efforts to direct CAR T cells against cancer proved disappointing.13

That gave way to cautious optimism and then considerable excitement, however, when investigators began testing second-generation therapies with CARs that target the B-lymphocyte antigen CD19, which is frequently expressed in many hematological cancers.

Initial trials of such agents against NHL demonstrated far better persistence although limited efficacy.14 These results led to the more recent trials against B-cell lymphomas and ALL that have made headlines around the world.

High Responses Attract Interest

CAR T-cell therapy typically begins by bringing the patient in for several hours of leukapheresis, a process in which the patient’s blood is drawn, the T cells are removed, and the remaining serum is returned to the patient. The T cells are sent to a laboratory, where the CARs are grafted on; the resultant CAR T cells are reproduced many times over before being injected back into the patient.The most common adverse events (AEs) arising from the current generation of CAR T therapies are cytokine release syndrome (CRS), neurologic toxicity, and Bcell aplasia.15 Severe side effects requiring lengthy hospital stays are common. Such reactions make CAR T-cell treatments punishing even by the standards of cancer care, but trials persist because some treatments have produced remarkable results for patients with no other effective options.

The patients in the ZUMA-1 trial,2 for example, all had aggressive refractory B-cell lymphoma. In the second of the 2 cohorts in the trial (n = 20), 36% of participants had received ≥5 prior therapies, 82% were refractory to their second-line

therapy, and 18% had relapsed on stem cell transplant. Yet this group of patients who achieved a 73% CR rate after receiving KTE-C19.

Grade ≥3 adverse events (AEs) were experienced by 91% of patients in cohort 2, and 73% of participants had serious AEs. A single episode of cardiac arrest was the only grade 5 event. CRSspecific symptoms, which were all grade 1/2, included pyrexia (82%), hypotension (27%), tachycardia (27%), and other events (18%). To treat CRS, 45% of patients received tocilizumab and 36% were treated with steroids, which resolved CRS for 9 of 10 patients.

These results generated much excitement at the 2016 ASH Annual Meeting, as did findings reported from the ELIANA trial.16 The primary analysis for the first 50 patients enrolled in the ELIANA trial indicated that the CR rate was 68% and the CRi rate was 14%. All patients with a CR/ CRi also tested negative for minimal residual disease (95% CI, 69-91; P <.0001). The 6-month overall survival rate was 89% (95% CI, 76-95) and the disease-free survival rate was 60%.

These patients also were heavily pretreated. More than half (56%) had received a prior stem cell transplant, and the median number of prior lines of therapy was 3 (range, 1-8). Patients had primary refractory (10%), chemorefractory (11%), and relapsed ALL (79%).

In terms of AEs, 79% experienced CRS, of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1-22) and lasted for a median of 8 days (range, 1-36). Fifty-nine percent of patients with CRS were admitted to the intensive care unit for a median of 8 days (range, 1-34).

To resolve CRS, patients required treatment with anti-cytokine therapy (51%), high dose vasopressors (33%), invasive ventilation (20%), and dialysis (12%).

Meanwhile, Juno is reporting strong results from several of its CAR T-cell therapies in development. The company and its partners have continued a trial of JCAR014 against CLL, a trial of JCAR018 against CD19-negative ALL, and trials of JCAR017 against pediatric ALL and NHL. The most recent results for JCAR014 against CLL come from a phase I study of heavily pretreated patients who had failed on ibrutinib. Follow-up tests showed that 4 of 19 patients evaluated for efficacy after JCAR014 and fludarabine/cyclophosphamide had a CR and 10 of 19 patients had a partial response.16

In the phase I TRANSCEND trial, JCAR017 demonstrated a 60% complete response rate in patients with relapsed or refractory CD19-positive NHL. 17 The study administered JCAR017 at various doses to patients with diffuse large B-cell lymphoma, grade 3b follicular lymphoma, and mantle cell lymphoma. The ORR with the lowest dose of the therapy was 80%. CRs were seen in patients with double- and triple-hit lymphoma and for 1 patient with CNS disease.

Hurdles to Widespread Adoption

There were fewer AEs seen with JCAR017 compared with other CD19-targeted CAR T-cell therapies. None of the enrolled patients experienced severe CRS. Thirty-six percent of patients had grade 1/2 CRS and just 1 participant required treatment with tocilizumab. Additionally, 5 patients (14%) had severe neurotoxicity, all of which resolved with treatment.As CAR T-cell therapies move toward FDA approvals, questions have arisen about whether the cost of the revolutionary new treatments will be a limiting factor. No CAR T-cell therapy has reached the market, so discussion about what pharmaceutical companies will charge for such treatments is necessarily speculative but financial analysts tend to estimate that the price will be several hundred thousand dollars.18

Part of this pricing stems from factors common to all new drugs, such as the high cost of trials, but much of it reflects the high cost of making a custom treatment from the individual T cells of each patient. Drugmakers continue to improve their manufacturing processes, so there’s hope that a combination of increasing competition and efficiency could drive down initially high treatment costs.

There is also hope that technology from Cellectis will allow for the mass production of “off-the-shelf” CAR T-cell therapies that begin with stem cells rather than individual patient donations. Indeed, this approach has drawn interest from Pfizer and other companies looking for a fast way to enter the market for CAR T-cell treatments.

Cai Xuan, PhD, an analyst who covers oncology and hematology for GlobalData, sees price as a potential barrier to widespread adoption of CAR T-cell therapy in the near term. “At present, even if you ignore all the questions about whether CAR T will have any real use against solid tumors, it’s hard to see how it would become a common treatment against the 43,000 or so hematological cancers diagnosed in the US each year,” said Xuan. “The only way it would replace transplant therapy as the standard of care for many of these cancers would be a head-to-head trial, which is not in the works right now and would be very expensive to conduct,” she said. “If the idea was to use CAR T in conjunction with transplant therapy to increase the cure rate, that could meet a lot of resistance from a reimbursement perspective.

Adding another half-million dollars to the cost of transplants that already cost $250,000 to $300,000 and are curative in some cases—the outcomes for that would have to be much better than doing the transplant alone to justify the cost. “That’s not to say CAR T definitely won’t turn out to be a widely applicable breakthrough at some point, but the evidence just isn’t there yet,” Xuan added.

References

  1. Kite Pharma initiates rolling submission of U.S. Biologics License Application (BLA) for KTE-C19, its Investigational anti-CD19 CAR-T therapy, for the treatment of patients with relapsed/ refractory aggressive B-cell non-Hodgkin lymphoma (NHL) [press release]. Santa Monica, CA: Kite Pharma, Inc; December 4, 2016. http://ir.kitepharma.com/releasedetail.cfm?Release- ID=1002522.
  2. Locke FL, Neelapu SS, Bartlett NL, et al. A phase 2 multicenter trial of KTE-C19 (anti-CD19 CAR T Cells) in patients with chemorefractory primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL): interim results From ZUMA-1. Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 998.
  3. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL[press release]. Basel, Switzerland: Novartis; December 4, 2016. https:// www.novartis.com/news/media-releases/novartis-presents-results- first-global-registration-trial-ctl019-pediatric-and Breakthrough therapies.
  4. Friends of Cancer Research. www.focr. org/breakthrough-therapies?title=&field_sponsor_value=&- field_year_value%5B%5D=5. Accessed February 10, 2017.
  5. Juno Therapeutics places JCAR015 phase II ROCKET trial on clinical hold [news release]. Seattle, WA: Juno Therapeutics, Inc; November 23, 2016. http://ir.junotherapeutics.com/phoenix. zhtml?c=253828&p=irol-newsArticle&ID=2225491.
  6. bluebird bio announces interim phase 1 dose escalation data for its anti-BCMA CAR T product candidate in patients with relapsed/ refractory multiple myeloma [news release]. Cambridge, MA: bluebird bio, Inc; November 30, 2016. http://investor. bluebirdbio.com/phoenix.zhtml?c=251820&p=irol-newsArticle& ID=2226688.
  7. Our focus: integrated product platforms with broad therapeutic potential. bluebird bio, Inc. https://www.bluebirdbio.com/ our-focus/. Accessed February 7, 2017. Cellectis announces first patient treated in phase 1 trial of UCART19 in pediatric acute B lymphoblastic leukemia (B-ALL) [news release]. New York, NY: Cellectis; June 20, 2016. http://www.cellectis.com/en/content/cellectis-announces- first-patient-treated-phase-1-trial-ucart19-pediatric- acute-b-1.
  8. Cellectis submits IND application for UCART123, an allogeneic gene edited CAR T-cell product candidate, in AML and BPDCN [news release]. New York, NY:
  9. Cellectis; January 3, 2017. http:// www.cellectis.com/en/content/cellectis-submits-ind-application- ucart123-allogeneic-gene-edited-car-t-cell-product-1.
  10. From the promise of immunotherapy, a pipeline of opportunity. Adaptimmune. http://www.adaptimmune.com/pipeline/pipeline- overview. Accessed February 7, 2017.
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  12. Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006;12(20 pt 1):6106-6115. doi:10.1158/1078-0432.CCR-06-1183.
  13. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor—modified T cells in lymphoma patients. J Clin Invest. 2011;121(5):1822- 1826. doi:10.1172/JCI46110.
  14. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321-3330. doi:10.1182/blood-2016-04-703751.
  15. Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 221.
  16. Abramson JS, Palomba L, Gordon LI, et al. Transcend NHL 001: Immunotherapy with the CD19-Directed CAR T-Cell Product JCAR017 Results in High Complete Response Rates in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 4192.
  17. Ward A, Crow D. Race to control costs of cancer therapy revolution. Financial Times. www.ft.com/content/ad76a316- 9cee-11e5-b45d-4812f209f861. Published December 7, 2015. Accessed February 7, 2017.