CAR T Cell Killing Tumor Cell

New Immunotherapy Research Presented at ASH Annual Meeting 2019

Breast Cancer Cell 500X500
Over 26,000 attendees walked the exhibit halls in this year’s ASH Annual Meeting in Orlando. Novel research findings on promising therapeutic approaches in lymphoma, myeloma and leukemia were presented by several City of Hope investigators during this meeting.
Preliminary Results from a Phase 1b Study of TAK-079, an Investigational Anti-CD38 Monoclonal Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM)
                          Amrita Y. Krishnan, M.D.
Investigating a new approach in the treatment of relapsed or refractory plasma cell proliferative diseases, this multicenter, phase 1 study focused on the role of TAK-079 in defeating myeloma cancer cells. TAK-079 is monoclonal antibody that targets CD38 protein found on the surface of myeloma cells, thereby triggering immune system to attack and kill cancer cells via antibody-dependent cellular cytotoxicity.
Of the 31 enrolled patients, 28 were evaluable for response. Data shows that TAK-079 had an objective response rate (ORR) of 43% in these patients with no infusion reaction and no drug-related lymphopenia or thrombocytopenia. Additionally, subcutaneous TAK-079 minimized treatment burden with the lo w volume (2 mL) injections performed in less than a minute, suggesting the potential for home-based self-administration.
Effective Novel Fto Inhibitors Show Potent Anti-Cancer Efficacy and Suppress Drug Resistance
                           Jianjun Chen, Ph.D. and Rui Su, Ph.D.
Fat mass and obesity-associated protein (FTO) was reported to be highly expressed in patients with acute myeloid leukemia (AML). Our researchers believe that this association may be important for treating AML. They tested a full library of 260,000 inhibitor compounds to using a structure-based virtual screening.
They narrowed down the candidate compounds to two, namely CS1 and CS2, which showed the most significant effects on inhibiting leukemia progression and prolonging survival. This was further tested on AML mouse models. Taken together, the study identified two potent small-molecules FTO inhibitors that have promising efficacy in treating leukemia and are subject to further research.
PET-Adapted Nivolumab or Nivolumab Plus ICE As First Salvage Therapy in Relapsed or Refractory Hodgkin Lymphoma

Alex Herrera, M.D.
A prospective, multicenter phase II trial testing a promising, sequential, immunotherapy first-line approach in treating relapsed/refractory Hodgkin lymphoma. This trial evaluates whether nivolumab (nivo) alone can be powerful enough to get a patient into remission without the need for chemotherapy prior to a transplant.
For patients who received nivolumab alone, the ORR was 78% and the complete response rate (CR) was 70%. Among 35 evaluable patients, 27 patients were also able to receive an autologous transplant directly after the trial. Nivo’s side effects were mild. They included fatigue (28%), rash (18%), and fever (15%). Therefore, nivo alone was an effective bridge to transplant in most patients, sparing them the toxicity of traditional high-dose chemotherapy.
Dynamic Assembly of a Feedback Complex to Regulate Oncogenic B-Cell Receptor-Signaling

Jaewoong Lee, Ph.D.
CD25 is a strong predictor of poor outcome in patients with B-cell malignancies and not in other types of cancer — yet the mechanistic role of CD25 remained unclear. This study analyzed the interaction between CD25 and BCR signaling. The experiment shows that CD25 binds downstream signaling molecules of BCR, and through these interactions, CD25 launches a previously unrecognized negative feedback loop to BCR signaling in response to antigen encounter in B cells.
In mouse models, treatment with a CD25-specific antibody drug-conjugate (ADCT-301) extends survival or eradicates drug-resistant B cell malignancies. As a result, CD25 is identified as a feedback regulator of oncogenic BCR-signaling, which paves the path for therapeutic targeting of CD25 in refractory B-cell malignancies.
Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T Cell Product: Updated Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib
Tanya Siddiqi, M.D.
While oral-targeted drugs have improved treatment outcomes for patients with chronic lymphocytic leukemia, some patients remain intolerant or resistant to therapy, and others fail to achieve a complete response. Our team set out to investigate novel CAR T cell therapy for this heavily pretreated patient population.
This phase I/II trial is evaluating the safety and efficacy of liso-cel CAR T cell therapy. Among the 22 patients evaluable for efficacy in phase I, an 82% ORR was achieved. A complete response was achieved by 45.5% of patients. Majority of patients achieved objective response by 30 days, which is considered a rapidly achieved response. Additionally, liso-cel toxicities were manageable. The phase II portion of the study is currently enrolling patients.
Burden of Long-Term Morbidity Borne by Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) — a Report from the BMT Survivor Study (BMTSS)
                          Saro H. Armenian, D.O., M.P.H.
A retrospective, comprehensive evaluation of the long-term severe chronic health condition in patients with AML who were treated with bone marrow transplant (BMT). Eligible patients included those that had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for over 2 years after BMT and were at least 21 years old at BMT. Participants were matched with a nearest-age sibling to constitute an unaffected compassion group. A 231-item survey was used for evaluation.
As a result, the burden of severe chronic health conditions was substantially higher in BMT survivors. The most common morbidities were subsequent malignant neoplasms and diabetes. Additionally, the incidence of severe chronic health condition following BMT for AML exceeds 50% at 10 years, and continues to increase with time, approaching 70% at 20 years post-BMT.
This study was able to address the knowledge gap of long-term quality of survival among patients with AML who had BMT, which reveals a need for appropriate resource allocation in early detection of these chronic conditions over time.
Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

Haris Ali, M.D.
While ruxolitinib, a potent JAK1/2 inhibitor, is approved to treat myelofibrosis, it has historically been discontinued pre-transplant in patients pursuing hematopoietic cell transplant (HCT). Because graft-versus-host disease is a major cause of mortality following HCT, this study sought to see if peri-transplant continuation of ruxolitinib could enhance outcomes. The primary objective of this single-arm, single-center pilot study (N=12) was to identify the maximum tolerated dose and recommend phase II dose.
In all patients, one-year overall survival was 80%, progression-free survival was 68% and non-relapse mortality was 21%. All patients engrafted (n=12), with the median time to neutrophils engraftment of 19 days for the 5 mg arm and 16 days for the 10 mg arm. Hematologic dose limiting toxicities were not observed at either dose level. In conclusion, early results indicate that ruxolitinib is safe and feasible at 10 mg BID in myelofibrosis patients undergoing HCT, with 100% engraftment and a low rate of acute GVHD. An expansion cohort of 6 patients at 10 mg is being recruited.
Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines

Elizabeth Budde, M.D., Ph.D.

Options are particularly limited for patients with B-cell non-Hodgkin lymphoma (NHL) who have relapsed or not responded to CAR T cell therapies. This is an expanded,
phase I, open-label, multicenter trial that tested the dose escalation of monsunetuzumab, a T cell bispecific antibody designed to engage T cells and redirect their cytotoxic activity against malignant B cells.
As a result, among the efficacy-evaluable patients across all dose levels, ORR and CR were 64.1% (41/64) and 42.2% (27/64) in indolent NHL patients and 34.7% (41/119) and 18.6% (22/119) in aggressive NHL patients, respectively. Side effects were tolerable. Therefore, preliminary data supports the possibility for retreatment with monsunetuzumab due to favorable tolerability and durable efficacy in this heavily pre-treated patient population.