Abstract 5546: A murine reactive version of TAK-573 (anti-CD38 attenuated IFNα fusion protein) shows immunomodulatory and antitumor activity, alone and in combination with standard-of-care agents, in IFNa-insensitive, immunocompetent murine multiple myeloma tumor models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.5546-5546
• Main Authors: Hara, Tomoya, Wong, Christina, Yu, Jie, Collins, Sabrina, Wang, Haiqing, Sugimoto, Hiroshi, Zhang, Hong, Bjorck, Pia, Curley, Michael D.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-5546

Background: Despite improvements in outcome for patients treated with triplet and quadruplet based regimens, multiple myeloma is still a relapsing and ultimately fatal disease. We previously reported that targeting an investigational attenuated form of IFNα, or Attenukine™, to multiple myeloma (MM) tumor cells via direct fusion to an anti-CD38 antibody (TAK-573) has direct anti-proliferative activity on MM cancer cells in vitro and induces robust and durable responses in MM xenograft tumor models, alone and in combination with standard-of-care (SOC) agents. Here, we further elucidate the broad immunomodulatory impact and antitumor activity of a murine reactive version of TAK-573, anti-mouse CD38-attenuated murine IFNα (mCD38-mATT), alone and in combination with SOC agents in immunocompetent murine tumor models of MM. Methods: Murine CD38 receptor expression and direct sensitivity to murine IFNα (mIFNα) of 2 murine MM cell lines were characterized. Murine MM cell line-derived tumor models were established in immunocompetent mice and antitumor activity of mCD38-mATT treatment was evaluated alone and in combination with approved SOC agents for MM. Pharmacodynamic changes in the tumor immune microenvironment post-treatment were determined using multicolor flow cytometry. Results: Both MM murine tumor cell lines were insensitive to direct mIFNα treatment, indicating a reliance on immune-mediated antitumor activity when tested in vivo. Immunoprofiling analyses post-administration with single-agent mCD38-mATT indicated increased prevalence and activation of NK cells in peripheral blood and increased intratumoral CD8+ T: Treg and CD8+ T: CD4+ T cell ratios, compared to anti-mCD38 antibody or murine IFNα alone. Follow-on experiments evaluating single-agent mCD38-mATT indicated modest activity on tumor growth in vivo. Combination administration of mCD38-mATT with SOC agents had increased anti-tumor activity compared to either single-agent administration alone. Conclusion: Administration of mCD38-mATT induced broad immunomodulation and antitumor responses, alone and in combination with SOC agents in immunocompetent mouse models, highlighting the impact of this agent on CD38+ cells, both tumor and immune. These results support further investigation of combination therapies in the ongoing clinical evaluation of TAK-573 in a Phase 1 trial in patients with relapsed refractory MM. Citation Format: Tomoya Hara, Christina Wong, Jie Yu, Sabrina Collins, Haiqing Wang, Hiroshi