Abstract CT146: First-in-human phase I combination of the IL-15 receptor super agonist complex ALT-803 with a therapeutic (anti-CD20) monoclonal antibody (mAb) for patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL)
Authors: Fehniger Todd A. , Hess Brian T. , Bachanova Veronika , Becker-Hapak Michelle , McClain Ethan , Berrien-Elliott Melissa , Wagner Julia , Bartlett Nancy L. , Kahl Brad , Mehta-Shah Neha , Cashen Amanda F. , Gao Feng , Conradi Kyle , Rock Amy D. , Jeng Emily K. , Hernandez Liza , Egan Jack O. , Rhode Peter R. , Wong Hing C. 
Published: August 2018

Abstract
Immunotherapy is an effective modality for cancer treatment. IL-15 is a cytokine that stimulates CD8+ T cell and NK cell survival, metabolism, and anti-tumor immunity. We hypothesized that IL-15 therapy will augment anti-cancer immune responses in concert with tumor-targeting therapeutic mAbs. Pre-clinical studies have shown that the IL-15 receptor super agonist complex, ALT-803, enhanced the anti-tumor effects of anti-CD20 mAb against iNHL in vitro and in vivo (Rosario M et al., Clin Ca Res, 2016). Here, we conducted the first clinical study combining ALT-803 with a tumor-targeting mAb, in patients with rel/ref iNHL. A total of 21 iNHL patients [N=16 FL (FLIPI low: 4, int: 4, high: 8), N=4 MZL, N=1 SLL] were treated. Median age was 64 years (range 54-81), median number of prior therapies was 2 (range 1-18), and 5 patients were refractory to prior anti-CD20 mAb therapy. Treatment included an induction cycle of 4 weekly doses of rituximab (375 mg/m2 intravenously, IV) and ALT-803. The ALT-803 dose levels were 1, 3, and 6 mcg/kg IV followed by 6, 10, 15, and 20 mcg/kg subcutaneously (SC, N=3 per dose level). In patients with SD, PR or CR, consolidation therapy with ALT-803 (at the same dose level) and rituximab was then administered every 8 weeks for 4 cycles. No dose limiting toxicities were observed, and the recommended phase 2 dose was 20 mcg/kg SC. Overall ALT-803 was well tolerated with no grade 4 or 5 adverse events. Grade 3 AEs (regardless of attribution to ALT-803) included transient hypertension (14%), anemia (5%), nausea (5%), chills (5%), fever (5%), neutropenia (5%), and hyperglycemia (5%). Patients who received ALT-803 SC had a self-limited injection site reaction. To date, best ORR was 10/21 (48%), with 7 CR, 3 PR, 8 SD (all with decreased tumor volume), and 3 PD. Of the 12 patients treated with SC ALT-803, only 1 patient had PD, with the remainder receiving ongoing consolidation. In the 5 rituximab-refractory patients we observed 1 CR, 2 SD (45% and 36% tumor volume decrease), and 2 PD. PK analysis showed that SC ALT-803 administration resulted in a lower Cmax and prolonged blood levels compared to IV. At the 15 and 20 mcg/kg SC dose levels of ALT-803, NK cells were significantly increased by percentage (mean peak 30+5%, 6-fold, P&lt;0.001) and number (mean peak 687+347/uL, 10-fold, P&lt;0.001). This was accompanied by a marked increase in proliferation (Ki67, 97+0.5%, P&lt;0.001) and activation (CD69, 10-fold, P&lt;0.01) in vivo. CD8+ T cell number (2-fold, P&lt;0.01) and proliferation (Ki67, 56+6%, P&lt;0.001) were also significantly increased, without increases in CD4+ or regulatory T cell numbers. Patient NK cells exhibited enhanced functional responses (degranulation and IFN-γ production) against anti-CD20 mAb coated NHL targets after ALT-803 administration, compared to pre-ALT-803 samples. NK cells (P&lt;0.05) and CD8 T cells (P&lt;0.05) were also increased at the 6 and 10 mcg/kg SC ALT-803 levels. Thus, the immunostimulatory IL-15-based agent ALT-803 may be safely combined with a therapeutic mAb to significantly enhance NK and CD8+ T cell number and function in patients with iNHL. Phase 2 testing is underway in iNHL. Clinical investigations combining ALT-803 with additional therapeutic mAbs, complementary types of immunotherapy, and in additional malignancies are warranted.
Citation Format: Todd A. Fehniger, Brian T. Hess, Veronika Bachanova, Michelle Becker-Hapak, Ethan McClain, Melissa Berrien-Elliott, Julia Wagner, Nancy L. Bartlett, Brad Kahl, Neha Mehta-Shah, Amanda F. Cashen, Feng Gao, Kyle Conradi, Amy D. Rock, Emily K. Jeng, Liza Hernandez, Jack O. Egan, Peter R. Rhode, Hing C. Wong. First-in-human phase I combination of the IL-15 receptor super agonist complex ALT-803 with a therapeutic (anti-CD20) monoclonal antibody (mAb) for patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT146.