ASH Clinical News January 2017 Annual Meeting Edition | Page 32

CAR T-Cell Therapy

Immunotherapy “ outsmarts ” tumor cells by optimizing the immune response to the malignancy ; CAR-modified T cells are just one type of immunotherapy approach under investigation .

“ CAR T cells are an amazing piece of biologic innovation based on the concept of harnessing T cells ’ amazing killing power and broadening their ability to recognize their target ,” explained Stephanie L . Goff , MD , a surgeon at the National Cancer Institute ( NCI ) who works with Senior Investigator Steven A . Rosenberg , MD , PhD , head of the NCI ’ s Tumor Immunology Section .

CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that allows the T cells to recognize tumor cells . A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain . When expressed in T cells , CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen ( HLA ) -independent manner . These cells then expand and become highly focused hunters and killers of specific cells , unlike the indiscriminate destruction wrought by classic chemotherapeutics .

“ By combining the killing power with the recognition of an antibody , we can engineer T cells to target cells with any antigen on their surface ,” Dr . Goff said . For hematologic malignancies , that means CAR T cells can easily attack markers like CD19 and CD22 , which are highly expressed in B-cell malignancies .

A number of different CARs have been tried , using different receptor designs and viral vectors . The early CARs consisted of only the T-cell receptor complex ( TCR ), while newer CARs incorporate costimulatory domains , such as CD28 or CD137 , that improve cell survival and proliferation . 3

TABLE . CD19-Directed CAR T-Cell Therapies in Advanced Development for B-Cell Malignancies

CAR T-Cell Product

JCAR015 , JCAR014 , JCAR017

Gamma-retrovirus , Lentivirus , Lentivirus

On the Road to the FDA

Many of the CARs in development – especially those that are furthest along clinically – are directed at CD19 , a cell-surface protein expressed on B cells and B-cell precursors . CD19 is expressed on the surface of most B-cell malignancies , which include some leukemias and myelomas , and most non-Hodgkin lymphomas ( NHLs ).

Three pharmaceutical companies have second-generation CAR T-cell products in advanced development ( TABLE ); each of which has teamed with an academic center : Kite Pharma with the NCI ; Novartis with the University of Pennsylvania ( UPenn ); and Juno Therapeutics with Memorial Sloan Kettering Cancer Center , Fred Hutchinson Cancer Research Center , and Seattle Children ’ s Hospital .

“ Four or five years ago , people would have looked at the idea of immunotherapy as complete science fiction . They might say , ‘ It ’ s too hard , complicated , boutique , [ and ] academic ,’” Dr . Grupp said . Now , though , with two products expected to file FDA applications in the first half of this year , he sees CAR T-cell therapies headed to the mainstream . “ One could be an accident , but with two , we might be heading toward a trend .”

CD19-directed , CAR-modified T cells have shown promise in relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia ( ALL ) and , to a lesser extent , benefit in relapsed / refractory chronic lymphocytic leukemia ( CLL ) and B-cell NHLs , including diffuse large B-cell lymphoma ( DLBCL ) and follicular lymphoma . 4 , 5

Ongoing investigations are attempting to expand these indications , including to ALL in children and adults . Treatment with CD19- targeted CAR T-cell therapies has produced remission rates as high as 94 percent in children and young adults with relapsed and refractory ALL . 6 “ This study also confirmed the high complete remission rate , including a disease-free survival rate of approximately 55 percent at one year ,” Dr . Grupp noted , adding that , “ beyond one year , we have not observed much disease recurrence .”

He explained that , while some research groups are investigating CAR T cells as a bridge to hematopoietic cell transplantation ( HCT ), at CHOP , researchers are trying to avoid transplants . “ Skipping bone marrow transplant and replacing it with immunotherapy is an attractive , exciting idea .”

In CLL and NHL , response rates are approximately 40 to 50 percent , with similar durability . In the most recent trial at NCI , Dr . Goff administered CAR T cells to 19 patients with DLBCL who were refractory to standard therapies or had undergone autologous HCT . Nine of those patients achieved complete remission , and all nine remain in remission past one year of follow-up . 4 “ This is a population of patients who was looking for salvage therapy , and nine of them don ’ t have active lymphoma anymore ,” Dr . Goff said .

MSKCC , Fred Hutchinson , Seattle Children ’ s Hospital

Juno Therapeutics

A Complicated and Individualized Process

CAR T-cell therapy is a multistep process that can take anywhere from a few days to several weeks . After leukapheresis is completed , the T cells are activated and expanded ex vivo , then genetically modified for stable CAR expression , typically with the use of retroviral or lentiviral transduction . These reprogrammed cells are expanded to obtain a therapeutic dose of CAR T cells to be infused into the patient .

Before that happens , the patient undergoes chemotherapy to deplete his or her own remaining T cells . “ The chemotherapy creates an environment within the body that is ‘ hungry ’ for T cells ,” Dr . Goff explained . “ The immune system is then generating the right kind of cytokines to help the CAR T cells proliferate and expand .”

Figuring out the right combination ( i . e ., which chemotherapy to use and what dose and what amount of re-engineered T cells to reintroduce ), though , is difficult , she said . For most

— STEPHANIE L . GOFF , MD

candidate CARs , this has been a long process of trial and error , sometimes with fatal results .

In the summer of 2016 , the FDA placed the phase II ROCKET trial of JCAR015 in adults with ALL on hold after two patients died of cerebral edema . The drug ’ s manufacturer ( Juno Therapeutics , Inc .) reported that the deaths were related to the addition of fludarabine to the pre-conditioning regimen , and the trial was allowed to continue after cyclophosphamide was used as a substitution . However , in November , Juno Therapeutics placed the trial on voluntary hold following two additional patient deaths from cerebral edema . These deaths , Juno Therapeutics reported , appeared to be correlated with the rapid proliferation of CAR T cells injected back into the body , and it is working with the FDA to determine next steps .

30 ASH Clinical News January 2017 Annual Meeting Edition