Interleukin-15 Production for Treatment of Patients with Metastatic Malignancy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

: A major development over the past 5 years and a future direction is our development of long-acting IL-15. Long-acting IL-15 (MS-IL-15): For IL-15 to be effectively used this activity requires continuous IL-15 exposure above a threshold concentration. Therefore, much effort has been devoted toward developing IL-15 agonist which after a single injection maintains the cytokine in a narrow therapeutic window for a long period. There are 2 prevailing forms of IL-15, ALT-803 (N-803) and Escherichia coli IL-15 by CIV. N-803 has an apparent t1/2 of 30 hours for subcutaneous (SC) administration. However, this dose-dependent rate of N-803 is likely due to a significant proportion of the drug being consumed by target alpha beta and gamma delta T cells. The bioavailability of N-803 is only about 3%; 97% of the administered SC N-803 never reaches the systemic circulation and may activate immune cells in the injection site. Due to this systemic impediment at 10 mcg/kg-the clinical dose, there is only a 5-and 6-fold increase in the number of NK and CD56bright NK cells respectively. This contrasts with the 38-fold increase in the number of circulating NK cells and 358-fold increase in the number of CD56bright NKs with Escherichia coli when administered by CIV. However, CIV is not patient or physician acceptable. Thus, neither of the IL-15 preparation approaches is satisfactory. To address these critical issues, we have joined with Daniel Santi, Professor UCSF, and President ProLynx LLC to develop a process where IL-15 has the dramatic activity of CIV and patient acceptability of N-803. In this process a macromolecular carrier is attached to a linker that is connected to IL-15 via a carbamate group. The alpha carbon has an acidic carbon-hydrogen bond (C-H) with a pKa, that is controlled by an electron withdrawing PK "modulator" MeSO2. Upon hydrogen ion catalyzed proton removal, a rapid beta elimination occurs to cleave the linker carbamate bond and release IL-15 containing the alpha propyl remnant. The long-acting IL-15 is injected SC where it serves as a depot to slowly release IL-15 to the systemic circulation. When 50 mcg of long-acting IL-15 was administered SC, the NK cells reached a high maximum at 5 to 7 days lasting 2 weeks and the CD44high CD8 T cells reached a maximum at day 7 lasting 3 weeks. Single administration of long-acting IL-15 administered SC provided dramatic additivity along with intralesional anti-CD40 in the TRAMP-C2 murine model of prostate cancer. Thus, we have achieved our goal of an agent that has marked activation of the expression of NK and CD44high CD8 T cells with once every 3 weeks SC administration. Future Plans: Along with Dr. Santi we are aggressively developing long-acting IL-15 for clinical trials in patients with malignancy. Initially long-acting IL-15 will be administered by monotherapy but we plan to develop long-acting IL-15 with the array of combination therapies defined below. IL-15 administered by combination therapy: IL-15 with intralesional agonistic anti-CD40 to yield tumor specific CD8 T cells as antitumor therapy. IL-15 was administered by CIV at 2 mg/kg/day for 10 days. It led to a 5.8-fold increase in the number of circulating CD8 T cells. However, this effect was not associated with evidence that CD8 T cells manifested antitumor activity. Gamma cytokines such as IL-15 induce the immunoregulatory SOCS3 checkpoint agent that lead to the paralytic depression of CD4 T-cell helper function, that is mediated through transient expression of SOCS3. This paralysis of CD4 helper cells inhibited the generation of tumor specific CD8 T cells. The role of CD4 helper cells could be provided by CD40 agonists. We showed with the TRAMP-C2 murine syngeneic tumor model that treatment with an agonistic anti-CD40 was additive with IL-15. In terms of antitumor activity there was a 10-fold increase in the number of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells. Anti-PD-1 was additive to the IL-15 combination. These results will be applied to cancer medicine by supporting a clinical trial in cancer patients utilizing IL-15, anti-PD-1 with intralesional optimized anti-CD40 in patients with refractory or relapsed malignancy in collaboration with Dr. Jeffrey Ravetch, The Rockefeller University. IL-15 in combination therapy with anticancer monoclonal antibodies: As noted above, IL-15 administration led to a dramatic increase in the number of circulating activated NK cells. However, such increases alone were not sufficient to produce antitumor efficacy, possibly because most tumors express self-class MHC I molecules that inhibit NK effector functions. Furthermore, there is a lack of tumor cell specific targeting by NK cells. Therefore, we plan to use the combination of IL-15 with antitumor specific monoclonal antibodies to increase their ADCC and anticancer efficacy. We have completed a combination clinical trial involving IL-15 and CAMPATH-1 (anti-CD52) (NCT03903135) in the treatment of patients with adult T cell leukemia. Furthermore, we have initiated clinical trials in patients with chronic lymphocytic leukemia and obinutuzumab in combination with rhIL-15, NCT03759184, IL-15 with avelumab (anti-PD-1) in patients with mature T-cell lymphoma NCT03905135, renal cell cancer NCT04150562, anti-IL-15 with mogamulizumab (anti-CCR4), NCT04185220 in patients with ATL and cutaneous T-cell lymphoma. It is hoped with combination therapy long-acting IL-15 and anti-CD40 on the one hand and with monoclonal antibodies on the other that IL-15 will take a prominent role in the treatment of patients with metastatic malignancy. The last 2 cycles have been exceptionally productive. I have completed and published the results of 13 clinical trials, have published 85 manuscripts in high-impact journals. Over my career I have presented 98 honorary named lectureships and keynote addresses. I have received 25 scientific prizes including the Paul Ehrlich Medal, the AAI-Ralph Steinman Award for Human Immunology Research, and the Artois-Baillet Latour Health Prize. Finally, I have been elected to 18 honorary societies including the American Society for Clinical Investigation, the Association of American Physicians, the National Academy of Sciences, the National Academy of Medicine and the American Academy of Arts and Sciences. Our work on IL-15 in T-cell malignancies contribute to the central goals of the Lymphoid Malignancies Branch. Work on this project was completed in FY22.