Abstract 5717
Background
We have generated a therapeutic anti-PD-L1/IL-15 fusion protein (KD033) by combining a proprietary, fully human, high affinity anti-PD-L1 antibody with human IL-15. We have also generated a surrogate KD033 by combining an anti-mouse PD-L1 surrogate antibody with human IL-15. Both KD033 and KD033 surrogate significantly increased CD8+ T, NK and NKT cells in peripheral blood in monkeys and mice respectively. KD033 surrogate treatment resulted in tumor clearance and generated memory responses in syngeneic mouse models of colon carcinoma. We examined the extent of memory responses in these KD033 surrogate-treated tumor-free mice and evaluated the molecular mechanisms of KD033 surrogate efficacy.
Methods
Mouse CT26 colon carcinoma cells were grown subcutaneously in Balb/c mice prior to intravenous treatments with fusion proteins. Tumor-free mice were re-challenged with tumors from the same genetic background. For immune gene expression analysis, tumors were isolated 7 days after treatments and analyzed using the mouse PanCancer IO 360 Gene Expression Panel from Nanostring.
Results
KD033 surrogate treatment was associated with increased cytotoxic lymphocyte infiltrations in tumors and the microenvironment. One hundred percent (100%) of KD033 surrogate-treated tumor-free animals rejected the same tumor without any additional treatments. Mice re-challenged with unrelated tumors from the same background were rejected or demonstrated reduction of tumor growth without further treatments. KD033 surrogate-treated tumors showed significant increases in expression of genes involved in cytokine, adaptive and inflammatory pathways and upregulation of immune gene signatures involving not only cytotoxic cells but also dendritic and B cells.
Conclusions
KD033 surrogate inhibited tumor growth inhibition and demonstrated evidence of epitope spreading. Broad activation of innate and adaptive immune responses in tumors was observed. These observations strongly support KD033 clinical development. A phase I clinical trial of KD033 is planned in 2H 2019.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Animal studies were conducted for Kadmon by Crown Bioscience Inc. with approved SOP and IACUC protocol. Nanostring platform analysis was done for Kadmon by Canopy Biosciences.
Funding
Kadmon Corporation, LLC.
Disclosure
S. Martomo: Full / Part-time employment: Kadmon Corporation. X. Feng: Full / Part-time employment: Kadmon Corporation. D. Lu: Full / Part-time employment: Kadmon Corporation. Z. Polonskaya: Full / Part-time employment: Kadmon Corporation. X. Luna: Full / Part-time employment: Kadmon Corporation. M.V. Poyurovsky: Full / Part-time employment: Kadmon Corporation. K. McCracken: Full / Part-time employment: Kadmon Corporation. F. Miyara: Full / Part-time employment: Kadmon Corporation. L. Li: Full / Part-time employment: Kadmon Corporation. S. Aggarwal: Full / Part-time employment: Kadmon Corporation. J. Patel: Full / Part-time employment: Kadmon Corporation.
Resources from the same session
5760 - Landscape of PD-L1 expression status in Chinese solid tumor patients.
Presenter: Yi Zhong
Session: Poster Display session 3
Resources:
Abstract
3733 - Anti-cancer and immunomodulatory effects of cobimetinib in triple negative breast cancer
Presenter: Chun-Yu Liu
Session: Poster Display session 3
Resources:
Abstract
4426 - Differential expression of immunoregulatory molecules and highly-associated cancer genes may provide novel insights into strategic trial design for therapeutics
Presenter: Jacob Adashek
Session: Poster Display session 3
Resources:
Abstract
2752 - Insights into the Tumor Immune Microenvironment using Tissue Phenomics to Drive Cancer Immunotherapy
Presenter: Martin Groher
Session: Poster Display session 3
Resources:
Abstract
5713 - Immune competent somatic mosaic model of colorectal cancer
Presenter: Stefania Napolitano
Session: Poster Display session 3
Resources:
Abstract
1898 - Genomic correlates of response to anti-PDL1 Atezolizumab in non-small-cell lung cancer OAK and POPLAR trials
Presenter: Hari Singhal
Session: Poster Display session 3
Resources:
Abstract
3246 - Erdafitinib (erda) versus available therapies in advanced urothelial cancer: A matching adjusted indirect comparison
Presenter: Yohann Loriot
Session: Poster Display session 3
Resources:
Abstract
3311 - High level of activity of Nivolumab anti-PD-1 immunotherapy and favorable outcome in metastatic/refractory MSI-H non-colorectal cancer: Results of the MSI cohort from the French AcSé program
Presenter: Christophe Tournigand
Session: Poster Display session 3
Resources:
Abstract
2314 - TP53 and ATM Co-mutation Predicts Response to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer
Presenter: Yu Chen
Session: Poster Display session 3
Resources:
Abstract
4692 - Immune cell biomarkers on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA NSCLC patients
Presenter: Raquel Laza-Briviesca
Session: Poster Display session 3
Resources:
Abstract