Features
Off to the CAR T Races
Bringing CAR T-Cell Therapies to Cancer Patients
August 30 , 2017 , marked a milestone for medicine : The cell-based gene therapy tisagenlecleucel became the first U . S . Food and Drug Administration ( FDA )– approved treatment that re-engineers a patient ’ s own T cells into focused cancer killers . 1 The decision followed the FDA ’ s Oncologic Drugs Advisory Committee ’ s unanimous vote to recommend the immunotherapy for approval ; in remarks , one panel member called it the “ most exciting thing I ’ ve seen in my lifetime .” 2
This approval “ marks an important shift in the blood cancer treatment paradigm ,” commented Kenneth Anderson , MD , president of the American Society of Hematology ( ASH ), in a press release . “ We now have proof that it is possible to eradicate cancer by harnessing the power of a patient ’ s own immune system .” 3
Less than two months later , tisagenlecleucel was joined by another CAR T-cell therapy : Axicabtagene ciloleucel was approved for the treatment of adult patients with relapsed or refractory large B- cell lymphoma after two or more lines of systemic therapy . 4
Breakthrough treatments inevitably raise challenging issues , and chimeric antigen receptor ( CAR ) T-cell therapies are no exception . ASH Clinical News spoke with scientists and clinicians to better understand the science , potential , and most pressing issues surrounding CAR T-cell therapies .
A First-in-Class Approval
A quick primer on CAR T-cell therapies : A patient ’ s T cells are harvested , re-engineered to express a recombinant receptor that targets a tumor-specific protein , and infused back into the patient ’ s body to proliferate and eradicate cancer cells .
The concept of “ training ” T cells to hunt and destroy cancer cells is the stuff of dreams for scientists who have spent their careers trying to take advantage of the innate immune system to combat disease . With the approval of the first CAR T-cell treatment , albeit for a discrete indication , that dream becomes a reality .
Pharmaceutical companies are racing to bring their candidate products to market . With the approval of tisagenlecleucel , Novartis was the first to reach the proverbial finish line . ( For a look at the other companies and therapies attempting to follow in its tracks , see the SIDEBAR on page 71 .)
Tisagenlecleucel ( formerly known as CTL019 and branded as Kymriah ) was developed by researchers at the University of Pennsylvania to use the 4-1BB costimulatory domain to enhance cellular responses . It is indicated for the treatment of children and young adults with B-cell precursor acute lymphoblastic leukemia ( ALL ) that is refractory or in second or later relapse . ALL is the most common childhood cancer , and relapsed ALL is a leading cause of cancer death in children . However , five-year survival for children and adolescents has increased over time and is now estimated at 85 percent . 5 For all the hype surrounding its approval , tisagenlecleucel is only approved for that small percentage who relapse . In the most recent data from the pivotal phase III ELIANA study , 83 percent of patients who received tisagenlecleucel achieved complete remission ( CR ) or CR with incomplete blood count recovery within three months . 6
“ We now have proof that it is possible to eradicate cancer by harnessing the power of a patient ’ s own immune system .”
— KENNETH ANDERSON , MD
“ Obviously , for the patients who need the therapy , the impact is great ,” said Navneet Majhail , MBBS , MD , director of the Blood and Marrow Transplant Program at Cleveland Clinic ’ s Taussig Cancer Institute in Ohio . However , he added , “ the larger , societal impact is going to be relatively small .”
Novartis plans additional filings for tisagenlecleucel in the U . S . and the European Union later this year , including an application for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma ( DLBCL ), based on interim results from the phase II JULIET study . At three-month follow-up , the overall response rate in adults with relapsed or refractory DLBCL was less than half what was seen for children with ALL – 45 percent – with 37 percent of patients achieving CR . 7
The company is actively studying other CAR T-cell therapies , including CTL119 , a humanized anti-CD19 CAR in early development for multiple B-cell malignancies , as well as CAR T-cell therapies for myeloid leukemias , multiple myeloma , and solid tumors .
Rolling Out CAR Ts Worldwide
When the FDA announced its decision on tisagenlecleucel , Novartis introduced a new pricing model and reimbursement plan for the product . The company is also busy establishing a network of treatment centers slated to include 32 fully certified centers by the end of 2017 . Only designated centers will be permitted to collect cells for tisagenlecleucel manufacturing and subsequently prescribe the product .
Dr . Majhail ’ s center , which was not part of the ELIANA trial but has participated in other CAR-T trials , is in the process of being approved to administer tisagenlecleucel as a commercial product .
As a transplant center that performs approximately 200 bone marrow ( BM ) transplants each year , he expects it to “ easily accommodate ” patients requiring CAR T-cell treatment . However , he suspects the complexity of the entire therapeutic process might make it difficult for non-transplant centers to become CAR T-cell providers .
“ Conceptually , the process [ of manufacturing and administering CAR T-cell therapy ] is like a BM transplant : You have to ensure the patient is a candidate , collect the T cells by apheresis , work with the cell-processing lab to send them to a production facility , receive them back , administer lymphodepleting chemotherapy , infuse the patients , and provide post-infusion care , including preventing and
70 ASH Clinical News November 2017