December 20, 2016: JUNO and CELG announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to investigational drug JCAR017 for the treatment of patients with relapsed/refractory (r/r) aggressive large B-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), not otherwise specified (de novo or transformed from indolent lymphoma), Primary Mediastinal B-cell Lymphoma (PMBCL) or Grade 3B Follicular Lymphoma. In addition, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) have granted JCAR017 access to the Priority Medicines (PRIME) scheme for r/r DLBCL.
JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain, which differentiates it from other CD19-directed CAR T product candidates in clinical development. Earlier this month, data from multiple phase I studies with JCAR017 in non-Hodgkin lymphoma and pediatric acute lymphoblastic leukemia were presented at the 58th American Society of Hematology Annual Meeting.
December 19, 2016: The biotechnology company Juno Therapeutics defeats Kite Pharma’s challenge to CAR T-Cell patent. Juno Therapeutics announced that it has defeated an attempt to invalidate a patent exclusively licensed by Juno that covers, among other things, a chimeric antigen receptor (CAR) T-cell used for the treatment of B-cell malignancies, and that it is suing Kite Pharma, Inc., seeking a declaratory judgment that Kite’s lead product candidate, KTE-C19, will infringe the patent when commercially produced.
In August 2015, Kite Pharma, Inc. filed an inter partes review in the U.S. Patent & Trademark Office in an attempt to invalidate U.S. Patent No. 7,446,190 by challenging all of its claims. Juno exclusively licenses the ‘190 patent, titled “Nucleic Acids Encoding Chimeric T Cell Receptors,” from Sloan-Kettering Institute for Cancer Research, an affiliate of Memorial Sloan-Kettering Cancer Center. The patent covers, among other things, a construct for a CD-19 targeted CAR T cell treatment that employs a CD28 costimulatory domain.The U.S. Patent & Trademark Office instituted a review of the patent, and on December 16, 2016, issued a final written decision upholding all the claims of the patent.
The lawsuit is being filed in the U.S. District Court for the District of Delaware. Juno and the Sloan Kettering Institute are represented by Irell & Manella LLP in both the IPR and the litigation.
December 6, 2016: Juno provided an update of key data from studies of its investigational chimeric antigen receptor (CAR) T-cell product candidates, presented at the 58th American Society of Hematology (ASH) Annual Meeting in San Diego, December 3-6, 2016.
We are encouraged by the safety and efficacy results we see with JCAR017 and JCAR014 in several B-cell malignancy settings, including in non-Hodgkin lymphoma, chronic lymphocytic leukemia, and pediatric acute lymphoblastic leukemia, and the possibilities suggested by early data in treating patients with CD19-negative disease, said Hans Bishop, Junos President, and CEO. We are also learning more about factors that contribute to efficacy and managing the toxicities associated with CAR T therapy and will apply what we learn to our broader development pipeline.
Pediatric Acute Lymphoblastic Leukemia (ALL): JCAR017Final results from the Phase I Pediatric Leukemia Adoptive Therapy-02 (PLAT-02) study with JCAR017 in children and young adults with relapsed or refractory (r/r) CD19-positive ALL were presented in an oral session by Rebecca Gardner, M.D., of Seattle Children’s Research Institute (Abstract #219), on Saturday, December 4. JCAR017 uses a defined CD4: CD8 cell composition and 4-1BB as the costimulatory domain, which differentiates it from other CD19-directed CAR T product candidates in clinical development.
The presentation updated data previously presented at ASCO in June 2016. It included 43 pediatric and young adult patients treated with JCAR017 who were evaluable for response.
Key results:40/43 (93%) patients experienced a minimal residual disease (MRD)-negative complete remission (CR).
In patients who received preconditioning with fludarabine/cyclophosphamide (flu/cy) lymphodepletion, the overall response (OR) rate was 14/14 (100%) patients. The estimated 12-month event-free survival is 50.8% (95%CI 36.9, 69.9) and overall survival (OS) is 69.5% (95%CI 55.8, 86.5).Severe cytokine release syndrome (sCRS) was observed in 10/43 (23%) patients.
A second study presented by Dr. Gardner examined toxicity management in the PLAT-02 trial (Abstract #586). In the study, two cohorts were given either anti-IL6 (tocilizumab) alone or the combination of tocilizumab and the steroid dexamethasone, with the goal of preventing sCRS. Results showed:
Both cohorts experienced similar overall rates of Grade 1-2 CRS following treatment: 21/23 (91%) in cohort 1 and 19/20 (95%) on in the early intervention group. In the tocilizumab arm, 7 of 23 (30%) patients experienced sCRS, versus 3/20 (15%) in the tocilizumab / dexamethasone arm.
Early intervention with immunomodulation appeared to decrease the rates of sCRS while preserving the previously observed high rates of MRD-negative CR.
Long-term persistence of CD19 CAR-T cells is protective against relapse.
Pediatric ALL: JCAR018Nirali N. Shah, M.D., of the National Cancer Institute, presented data from a Phase I study of JCAR018, a CAR T cell product candidate targeting CD22, in 16 pediatric patients with r/r CD19-negative ALL (Abstract #650) on Monday, December 5. The study is the first to evaluate CAR T cell therapy in patients expressing CD22. All of the patients had been previously treated with anti-CD19 CAR T cell therapy and had already undergone at least one allogeneic stem cell transplant.
The primary adverse event was grade 1-2 cytokine release syndrome, with no severe or irreversible neurotoxicity. There was one death due to sepsis in a patient after resolution of CRS.
3/9 (33%) patients are in ongoing remission ranging 3-12+ months.
Results showed 7/8 (88%) patients achieved an MRD-negative CR with flu/cy lymphodepletion followed by JCAR018 at dose level 2 (1 x 106 transduced CAR T cells/kg).
The study continues to enroll patients. Juno is currently testing pre-clinical constructs to understand better the optimal way to target these two antigens in the same product.
Diffuse Large B-Cell Lymphoma (DLBCL): JCAR017In a poster presentation on Monday, December 5, Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, presented results from the Phase I TRANSCEND study in patients with r/r DLBCL, follicular lymphoma grade 3B or mantle cell lymphoma (MCL) who were treated with flu/cy lymphodepletion and JCAR017.
Topline results included a 12/20 (60%) complete response in patients with r/r DLBCL (N=19) and follicular lymphoma grade 3B (N=1) treated with a single dose of JCAR017 at dose level 1 (5×107 cells). No sCRS was observed; grade 3-4 neurotoxicity was seen in 3/22 (14%) patients, all of whom received the steroid dexamethasone for neurotoxicity. Also, the side effect profile plus cell persistence suggests the potential for combination therapy.
The Phase I TRANSCEND trial continues, enrolling more patients at dose levels 1 and 2. Juno intends to initiate a pivotal trial in the U.S. in patients with r/r DLBCL in 2017.Chronic Lymphocytic Leukemia (CLL): JCAR014In an oral presentation on Saturday, December 4, Cameron Turtle, M.B.B.S., Ph.D., of the Fred Hutchinson Cancer Research Center, reported on results from a Phase I study of heavily pretreated patients with CLL who failed treatment with ibrutinib, the standard-of-care treatment for CLL. Fifteen of 17 (88%) efficacy-evaluable patients who had bone marrow disease at the start of the trial and treated with flu/cy and the two lowest doses of JCAR014 had a complete marrow response by flow cytometry. Fourteen of the complete bone marrow response patients had a response assessment by the more sensitive method of IgH deep sequencing, with 7/14 (50%) having no detectable disease. All seven of these patients are alive and progression free with follow-up ranging from 3 to 26 months.
Two of 24 (8%) patients developed grade 3-5 sCRS and 6/24 (25%) patients developed grade 3-5 severe neurotoxicity. There was one treatment-related mortality (4%) in the trial in a patient who received flu/cy lymphodepletion, with both grade 5 CRS and cerebral edema.
Plans to study JCAR014 in combination with ibrutinib in CLL are underway, with a cohort expected to begin enrollment in early 2017. Juno is evaluating the use of this data with JCAR014 as a monotherapy and in combination with ibrutinib in support of a potential Juno-sponsored trial with JCAR017 in CLL.
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Juno Therapeutics, Inc., a biopharmaceutical company, engages in developing cell-based cancer immunotherapies.