Based on the largest study of CD19-directed chimeric antigen receptor (CAR) T-cell therapy, the U.S. Food and Drug Administration (FDA) has accepted lisocabtagene maraleucel, also known as liso-cel, JCAR017 and Anti-CD19 CAR T-Cells* for priority review.

Liso-cel is Bristol-Myers Squibb’s autologous anti-CD19 chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after at least two prior therapies.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of August 17, 2020.

Liso-cel is an investigational CAR T-cell therapy designed to target CD19, which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells.

Lisocabtagene maraleucel
Lisocabtagene maraleucel aims to target CD19-expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-ζ (zeta) T-cell activation domain.

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The agent consists of individually formulated CD4+ and CD8+ cell suspensions that are administered in a defined composition, using controlled doses of cells. After apheresis, patient cells are immunomagnetically selected and separated based on CD4+ or CD8+ expression. The 2 cell types are separately transduced with a lentiviral vector, followed by expansion. The modified cells are then administered using equal numbers of CD4-positive and CD8-positive cells.

The defined composition of CAR-positive viable T-cells, which consists of the two subtypes of T-cells CD8+ and CD4+, in lisocabtagene maraleucel that may behave differently, and, as a result, reduce product variability.  That reason is that CD8+ T-cells have a cancer-killing effect, while CD4+ T-cells produce chemical messages that boost T-cell production. However, while the clinical significance of defined composition is, so far, unknown, finding the right ratio of CAR T-cells created from these subtypes may potentially impact the efficacy and safety of these treatments.

Patient’s Own T-cells
Lisocabtagene maraleucel uses the patient’s own healthy T-cells to fight cancer. The CAR-T technology is designed to re-program T-cells to target cells that express a specific protein (CD19) that is commonly found on the target cancer cells.

To produce lisocabtagene maraleucel, T-cells are first extracted from the patient’s own blood and are genetically modified to produce a CAR protein. The CAR consists of an antibody, a protein that interacts with CD19, which can stimulate a signaling domain, sending a message to the T-cell when CD19 binds to it.

Before the modified T-cells being returned to the patient, they receive lymphodepleting chemotherapy. This allows the creation of a better environment for the modified T-cells to expand and persist in the body. Liso-cel is administered as an intravenous infusion and is designed to track down and destroy the cancer cells

Critical need
“There remains a critical need for additional therapies in large B-cell lymphoma, particularly for relapsed or refractory patients,” noted Stanley Frankel, M.D., senior vice president, Cellular Therapy Development, Bristol-Myers Squibb.

Lisocabtagene maraleucel (liso-cel; JCAR017; Anti-CD19 CAR T-Cells) is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, [1][2] which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells. [3][4][5] Liso-cel CAR T-cells aim to target and CD-19 expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-zeta T-cell activation domain. [1][2][6][7][8][9] The defined composition of liso-cel may limit product variability; however, the clinical significance of defined composition is unknown. [1][10] Image Courtesy: 2019/2020 Celgene/Juno Therapeutics / Bristol Meyers Squibb.
“Based on the TRANSCEND NHL 001 data, liso-cel has the potential to expand treatment options for those affected by this aggressive blood cancer who did not respond to initial therapies or whose disease has relapsed. This BLA acceptance and Priority Review designation is an important step as we work to improve treatment for these patients in need,” Frankel added.


The BLA, submitted by Juno Therapeutics, a wholly-owned subsidiary of Bristol-Myers Squibb Company, is based on the safety and efficacy results from the TRANSCEND NHL 001 trial, evaluating liso-cel in 268 patients with R/R large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade lymphoma, primary mediastinal B-cell lymphoma, and Grade 3B follicular lymphoma.

The TRANSCEND NHL 001 (NCT026310444) is the largest open-label, multicenter, pivotal phase I study of CD19-directed CAR T-cells to support a BLA to date and was recently the subject of an oral presentation by Key safety and efficacy results in patients with R/R large B-cell lymphomas (LBCL), presented by Jeremy Abramson, MD, from the Massachusetts General Hospital Cancer Center, at the 61st American Society of Hematology Annual Meeting and Exposition (ASH 61; Abstract #241).

During the same meeting, David G. Maloney, MD, at Fred Hutchinson Cancer Research Center, presented data on health-related Quality of Life (hrQoL) and health utility in patients with R/R aggressive B-cell NHL enrolled in the TRANSCEND NHL 001 study. The data he presented incorporated patient-reported outcomes (PRO) assessments to evaluate the impact of liso-cel on symptoms, (hrQoL), and health utility in patients with high disease burden and toxicities associated with prior chemotherapy and HSCT (ASH 61; Abstract 66).

Dose levels
In the TRANSCEND NHL 001 study, lisocabtagene maraleucel was administered as after lymphodepleting chemotherapy, at 1 of 2 dose levels (DL): DL1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Efficacy was evaluated per the Lugano criteria. Patients achieving a complete response could be treated with liso-cel upon progressive disease.

The study was designed to determine the safety, antitumor activity, and pharmacokinetics of liso-cel in patients with R/R B-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common of large B-cell lymphomas as well as HGL, PMBCL, Grade 3B FL.

Mantle cell lymphoma is investigated in a separate cohort.

The primary outcome measures included treatment-related adverse events, dose-limiting toxicities, and objective response rate. Key secondary outcome measures included complete response rate, duration of response, and progression-free survival.

The TRANSCEND program is a broad clinical program evaluating liso-cel in multiple disease states and treatment stages.

Priority review
According to the FDA, a Priority Review designation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

Liso-cel was previously granted Breakthrough Therapy and Regenerative Medicine Advanced Therapy designations by the FDA for R/R aggressive large B-cell non-Hodgkin lymphoma, including DLBCL, not otherwise specified (de novo or transformed from indolent lymphoma), PMBCL or Grade 3B FL, and Priority Medicines (PRIME) scheme by the European Medicines Agency for R/R DLBCL.

* Lisocabtagene maraleucel (liso-cel; JCAR017; Anti-CD19 CAR T-Cells) was originally developed by Juno Therapeutics, at the time a wholly-owned subsidiary of Celgene, before both companies were taken over by being Bristol-Myers Squibb.

Clinical trial
Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001) – NCT02631044

[1] Abramson JS, Palomba ML, Gordon LI, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort [ASH abstract 581]. Blood. 2017;130(suppl 1).
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[7] Davila ML, Bouhassira DC, Park JH, et al. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int J Hematol. 2014;99(4):361–371. doi:10.1007/s12185-013-1479-5
[8] Maus MV, June CH. Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Clin Cancer Res. 2016;22(8):1875–1884. doi:10.1158/1078-0432.CCR-15-1433
[9] Maloney DG, Abramson JS, Palomba ML, et al. Preliminary safety profile of the CD19-directed defined composition CAR T cell product JCAR017 in relapsed/refractory aggressive B-NHL patients: potential for outpatient administration. Blood 2017; 130(Suppl. 1): 1552.
[10] Cheadle EJ, Hawkins RE, Batha H, O’Neill AL, Dovedi SJ, Gilham DE. Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. J Immunol. 2010;184(4):1885–1896. doi:10.4049/jimmunol.0901440

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