FEATURE treating complications . All these processes are essentially what we do in BM transplantation right now .”
Manufacturing Marvels
Manufacturing CAR T-cell therapies is no simple feat , requiring several carefully executed steps . “ These products must be temperature-controlled at all times during preparation , shipping , and administration , and can only be manipulated under aseptic conditions ,” explained Marcela V . Maus , MD , PhD , of the Massachusetts General Hospital , and Sarah Nikiforow , MD , PhD , of the Dana-Farber Cancer Institute , in a recent paper published in the Journal for Immuno- Therapy of Cancer . 8
“Obviously , for the patients who need the therapy , the impact is great . The larger , societal impact is going to be relatively small .”
— NAVNEET MAJHAIL , MBBS , MD
Drs . Maus and Nikiforow ( a 2014 ASH Scholar Award recipient ) are members of the Foundation for the Accreditation of Cellular Therapy , an organization established by the International Society for Cellular Therapy and the American Society of Blood and Marrow Transplantation for voluntary inspection and accreditation in the field of cellular therapy . The agency established new standards for the use of immune effector cells , specifying the clinical and quality infrastructure required for safe administration of those therapies .
In the early days of tisagenlecleucel , cell processing was performed at the University of Pennsylvania , the academic center where it was developed . Once tisagenlecleucel advanced to later-phase trials , Novartis transferred manufacturing to their facility in Morris Plains , New Jersey ; to date , more than 250 patients in 11 countries across various indications have received T-cell products manufactured at the Novartis site . 9
The manufacturing process includes cryopreservation of a patient ’ s harvested cells , giving treating physicians and centers greater flexibility to initiate CAR T-cell therapy based on the individual patient ’ s condition . “ Cryopreservation also allows for manufacturing and treatment of patients from around the world ,” according to the pharmaceutical company , which also has a manufacturing facility in Leipzig , Germany .
Manufacturing failure does happen . In the most recent data on tisagenlecleucel , seven of 88 patients ( 8 %) enrolled in the trial were not infused as a result of insufficiently formulated CAR T-cell product . 5 Early reported manufacturing failure rates in hematology / oncology studies using several different CAR T-cell products ranged from 2 percent to 14 percent . 10
The most common reason for manufacturing failure was “ inability to achieve targeted dose ,” most commonly caused by an inadequate number of T cells in the incoming apheresed product , poor selection of T cells on day zero of manufacturing , or irreversibly impaired T cells ( i . e ., no response to stimulation in culture ). In addition , more general causes , such as microbial contamination , equipment-related cell loss , high endotoxin level , and accidents , can ruin CAR T-cell products for clinical use .
“ We have much more difficulty growing these cells in culture with certain diseases , and that is usually related to the amount of prior therapy that the patients have received ,” Adrian P . Gee , PhD , professor in the Department of Pediatrics , Section of Hematology-Oncology at Baylor College of Medicine in Houston , Texas , told ASH Clinical News . Indeed , the cited 14 percent failure rate was seen in an early study that enrolled heavily treated lymphoma patients .
Dr . Gee also directs the Clinical Applications Laboratory and the Cell Processing and Vector Production Core Laboratory at the Center for Cell and Gene Therapy at Baylor , which is conducting preclinical and early clinical research in CAR T cells for multiple indications , including neuroblastoma . They produce their own de novo CAR T cells in their facility .
One sure way to simplify and more readily scale up manufacturing is to develop an “ off-the-shelf ” allogeneic CAR T-cell product that uses immune cells from a healthy donor . It would be “ very attractive to just generate the cells from healthy donors , and then they ’ d be immediately available to treat a patient ,” said Dr . Gee .
This process also would eliminate the time and costs involved in production : Allogeneic products could potentially be manufactured in bulk , ready to use whenever a patient needs them . Experimental allogeneic CAR T-cells are being evaluated in clinical trials but have shown little success . On September 4 , Cellectis reported that the FDA had placed a clinical hold on its phase II studies of UCART23 in patients with
The CAR T Pack in Pursuit
After gaining U . S . Food and Drug Administration ( FDA ) approval for tisagenlecleucel , Novartis has become the “ leader of the pack ” in the field of gene therapy , but several other pharmaceutical manufacturers are drafting on Novartis ’ s success . On October 18 , 2017 , Kite Pharma , became the lead CAR T-cell manufacturer , at least from the perspective of patient impact . 1
The company received FDA approval for axicabtagene ciloleucel ( axicel , formerly known as KTE-C19 ) to treat patients with three subtypes of aggressive non-Hodgkin lymphoma ( NHL ), relapsed or refractory diffuse large B-cell lymphoma ( DLBCL ), transformed follicular lymphoma , and primary mediastinal B-cell lymphoma in patients who are ineligible for autologous hematopoietic cell transplantation . This marks the first approval in adults and affects a patient population that is approximately more than quadruple the size of tisagenlecleucel ’ s . Kite Pharma has also submitted for approval in Europe and expects a decision and potential launch there in early 2018 .
The axi-cel approval was based on data from the ZUMA-1 trial , which enrolled 111 patients from 22 institutions , 101 of whom ( 91 %) received axi-cel . 2 The trial met its primary endpoint with an objective response rate ( ORR ) of 82 percent after a single infusion . At a median followup of 8.7 months , 44 percent of patients showed continued response , including 39 percent who were in complete remission .
Kite Pharma is planning for a “ controlled ” launch of axi-cel at 20 sites , with plans to extend to 72 academic centers within a year of FDA approval . The company is already working to secure reimbursement agreements with payers so that sites can begin prescribing axi-cel “ within days ” of approval .
There are approximately 40 additional companies , many in partnership with academic institutions , actively developing chimeric antigen receptor ( CAR ) T-cell therapies for a diverse set of indications , though some of the efforts have been sidelined by safety concerns .
Juno Therapeutics was an early leader in the CAR T-cell race with JCAR015 for patients with acute lymphocytic leukemia ( ALL ), but lost ground when a series of toxicity-related setbacks culminated in the decision to halt the JCAR015 development program . The company then pivoted to focus on the rest of its deep CAR T-cell pipeline , like JCAR017 . Data from the phase I TRANSCEND study presented earlier this year showed an ORR of 86 percent and a complete response rate of 59 percent in patients with relapsed or refractory DLBCL treated with JCAR017 . 3
Juno Therapeutics has 11 ongoing CAR T-cell trials , covering a range of indications from NHL , pediatric ALL , multiple myeloma , acute myeloid leukemia ( AML ), non-small cell lung cancer / mesothelioma , pediatric neuroblastoma , ovarian cancer , breast cancer , and lung cancer . All candidates are in phase I trials , except two that are in phase I / II trials . 4
The CAR T-cell products furthest along in development target the CD19 antigen , but companies are exploring alternate targets . For instance , Juno Therapeutics ’ pipeline includes agents that target :
• CD22 in NHL and pediatric ALL
• WT1 , an intracellular protein that is overexpressed in a number of cancers , including AML and non-small cell lung , breast , pancreatic , ovarian , and colorectal cancers
• MUC16 , a protein overexpressed in most ovarian cancers
• B-cell maturation antigen , which is expressed on all plasma cells , including cancerous plasma cells in myeloma
REFERENCES
1 . U . S . Food and Drug Administration news release , August 20 , 2017 . Accessed September 29 , 2017 , from https :// www . fda . gov / NewsEvents / Newsroom / PressAnnouncements / ucm574058 . htm .
2 . Locke FL , Neelapu SS , Bartlett NL , et al . Clinical and biologic covariates of outcomes in ZUMA-1 : a pivotal trial of axicabtagene ciloleucel ( axi-cel ; KTE-C19 ) in patients with refractory aggressive non-Hodgkin lymphoma ( r-NHL ). Abstract # 7512 . Presented at the 2017 ASCO Annual Meeting , June 5 , 2017 ; Chicago , IL .
3 . Abramson JS , Palomba ML , Gordon LI , et al . High CR rates in relapsed / refractory ( R / R ) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 ( TRANSCEND NHL 001 ). Abstract 128 . Presented at the 14th International Conference on Malignant Lymphoma , June 17 , 2017 ; Lugano , Switzerland .
4 . Juno Therapeutics . “ Developing best-in-class therapies .” Accessed October 3 , 2017 , from https :// www . junotherapeutics . com / our-pipeline /.
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