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1O - Harnessing innate immunity in cancer therapies: The example of natural killer cell engagers
- Eric Vivier (Marseille, France)
Abstract
Background
Most immunomodulatory approaches have focused on enhancing T-cell responses, by immune checkpoint inhibitors, chimeric antigen receptor T cells or bispecific antibodies. Although these therapies have led to exceptional successes, only a minority of cancer patients benefit from these treatments, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate immune responses in immunity, harnessing these responses opens up new possibilities for tumor control. Antibody engineering provides us with great opportunities to induce synthetic immunity by harnessing the biological functions of innate immune cells, in particular by boosting the capacity of Natural Killer (NK) cells to kill tumor cells directly and to stimulate T-cell responses indirectly.
Methods
We designed NK cell engagers (NKCEs) to optimize NK cell antitumor functions by binding to three activating receptors, NKp46, CD16 and IL-2R, on NK cells, and one antigen on tumor cells. The IL-2R interacting element is a variant of interleukin-2 (IL-2v) unable to bind the α-subunit of its receptor to limit regulatory T cell activation and IL-2Rα-mediated toxicity.
Results
In vitro, NKCE-IL2v promoted IL-2R signaling preferentially in NK cells, inducing primary human NK cell proliferation and cytolytic activity, and the secretion of cytokines and chemokines only after binding to the tumor target. In mouse models of both invasive and solid tumors, NKCE-IL2v induced NK cell proliferation and accumulation at the tumor bed, and had a higher anti-tumor efficacy than approved therapeutic antibodies targeting the same tumor antigen. Mechanistically, incorporating NKp46-, CD16- and IL-2 receptor-binding moieties in the same molecule, was essential for strong activity. In non-human primates, CD20-directed NKCE-IL2v resulted in sustained CD20+ B-cell depletion with minimal systemic cytokine release and no clinical sign of toxicity.
Conclusions
Tetrafunctional NKCE-IL2v thus constitutes a synthetic technological platform combining the induction of NK cell proliferation and effector functions without toxicity, supporting its clinical development for next-generation cancer immunotherapies.
Legal entity responsible for the study
Innate Pharma.
Funding
Innate Pharma.
Disclosure
E. Vivier, M. Vetizou, A. Blanchard Alvarez, G. Habif, C. Bonnafous, A. Represa, B. Rossi, S.L. Cornen, A. Morel, I. Perrot, Y. Morel, L. Gauthier, O. Demaria: Financial Interests, Personal, Full or part-time Employment: Innate Pharma.
2O - Penpulimab, an IgG1 anti-PD-1 antibody with Fc-engineering to eliminate effector functions and with unique epitope and binding properties
- Baiyong Li (Zhongshan, China)
Abstract
Background
Currently marketed anti-PD-1 antibodies are typically IgG4 isotype, of which bindings to FcγRs and CH3 region instability might lead to compromise on efficacy and safety. Penpulimab is a humanized IgG1 anti-PD-1 antibody engineered at the Fc region to eliminate binding to FcγRs and C1q, and thus avoid antibody dependent cell-mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to minimize lymphocyte loss, and to avoid antibody dependent cytokine release (ADCR) such as IL-8 and IL-6, which are known to associate with irAEs and poor prognosis in checkpoint blocking immunotherapy.
Methods
Binding kinetics of penpulimab to C1q, FcγRIa, FcγRIIa_H131, FcγRIIa_R131, FcγRIIb, FcγRIIIa_V158 and FcγRIIIa_F158 were measured by Fortebio. ADCC, ADCP and CDC activities were determined in cellular assays. IL-8, IL-6 from macrophage, and IFN-γ and IL-2 from PBMCs were detected by ELISA. Binding kinetics of penpulimab to human PD-1 was determined by Biacore, and epitope/paratope mapping of PD-1/penpulimab was investigated using X-ray crystallography.
Results
Penpulimab exhibited no binding to FcγRIa, FcγRIIa_H131, FcγRIIb, FcγRIIIa_V158, FcγRIIIa_F158 or C1q, and eliciting no apparent ADCC, ADCP or CDC. Additionally, penpulimab induced no remarkable IL-6 and IL-8 release by macrophages in contract to large amount of these cytokines induced by anti-PD-1 antibodies with IgG4 isotype. Unexpectedly, penpulimab is shown in the co-crystal study to bind to human PD-1
Conclusions
Penpulimab, a PD-1 antibody with IgG1 isotype and Fc engineering, exhibits no Fc receptor mediated effector functions including ADCC, ADCP, and ADCR, and has robust T cell stimulating activity via blocking of PD-1.
Editorial acknowledgement
Tianjing Zheng, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Legal entity responsible for the study
Akeso Biopharma Co., Ltd.
Funding
Akeso Biopharma Co., Ltd.
Disclosure
B. Li, Z. Huang, X. Pang, T. Zhong, C. Jin, N. Chen, S. Ma, X. He, D. Xia, X. Jin, Z. Wang, Y. Xia: Financial Interests, Personal, Full or part-time Employment: Akeso Biopharma Co., Ltd.
Invited Discussant 1O and 2O
- Sophie Papa (London, United Kingdom)
Q&A and live discussion
- Sophie Papa (London, United Kingdom)
3O - Patient-derived micro-organospheres (MOS) recapitulate tumor microenvironment and heterogeneity for precision oncology
- Shengli Ding (Durham, United States of America)
Abstract
Background
Preclinical models that can recapitulate patients’ intra-tumoral heterogeneity and microenvironment are crucial for tumor biology research and drug discovery. In particular, the ability to retain immune and other stromal cells in the microenvironment is vital for the development of immuno-oncology assays. However, current patient-derived organoid (PDO) models are largely devoid of immune components.
Methods
We first developed an automated microfluidic and membrane platform that can generate tens of thousands of micro-organospheres (MOS) from resected or biopsied clinical tumor specimens within an hour. We next characterized growth rate and drug response of MOS. Finally, extensive single-cell RNA-seq profiling were performed on both MOS and original tumor samples from lung, ovarian, kidney, and breast cancer patients.
Results
MOS derived from clinical tumor samples preserved all original tumor and stromal cells, including fibroblasts and all immune cell types. Single-cell analysis revealed that unsupervised clustering of tumor and non-tumor cells were identical between original tumors and the derived MOS. Quantification showed similar cell composition and percentages for all cell types and also preserved functional intra-tumoral heterogeneity. An automated, end-to-end, high-throughput drug screening pipeline demonstrated that matched peripheral blood mononuclear cells (PBMCs) from the same patient added to MOS can be used to assess the efficacy of immunotherapy moieties.
Conclusions
Micro-organospheres are a rapid and scalable platform to preserve patient tumor microenvironment and heterogeneity. This platform will be useful for precision oncology, drug discovery, and immunotherapy development.
Legal entity responsible for the study
The authors.
Funding
NIH.
Disclosure
All authors have declared no conflicts of interest.
1800O - Multi-omic characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation
- Álvaro Quintanal-Villalonga (New York, United States of America)
Abstract
Background
Lineage plasticity facilitates therapeutic resistance in multiple cancers. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations. The incidence of LUSC transdifferentiation in
Methods
We performed multi-parameter profiling of microdissected histological components of mixed histology (LUAD/LUSC) tumors, together with pre-/post-transdifferntiation clinical samples, including detailed genomic, epigenomic, transcriptomic and proteomic characterization. Clinical findings were validated in preclinical models including cell lines and patient-derived xenograft treatments.
Results
Our results suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events, and indicate that the resulting squamous tumors retain transcriptomic and methylation profiles of their previous LUAD state. We observed coordinated upregulation of PI3K/AKT, MYC and PRC2 pathway genes in the LUSC component of mixed histology tumors. Concurrent activation of PI3K/AKT and MYC induced squamous features in
Conclusions
Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and promising therapeutic targets to constrain or prevent lineage plasticity in this setting.
Legal entity responsible for the study
The authors.
Funding
Supported by NCI R01 CA197936 and U24 CA213274 (CMR), the SU2C/VAI Epigenetics Dream Team (CMR), the Druckenmiller Center for Lung Cancer Research (CMR, TS, AQV), Parker Institute for Cancer Immunotherapy grant (TS); International Association for the Study of Lung Cancer grant (TS), NIH K08 CA-248723 (AC). We acknowledge the use of the Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. We also acknowledge Maria Corazon Mariana and Emily Lin from the PPBC Biobank for their invaluable help. The PPBC Biobank and Pathology Core Facility are supported by the NCI Cancer Center Support Grant P30-CA008748.
Disclosure
H.A. Yu: Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Daiichi Sankyo; Financial Interests, Advisory Role: Janssen; Financial Interests, Advisory Role: Blueprint Medicine. C.M. Rudin: Financial Interests, Advisory Role: Amgen; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Epizyme; Financial Interests, Advisory Role: Genentech/Roche; Financial Interests, Advisory Role: Ipsen; Financial Interests, Advisory Role: Jazz; Financial Interests, Advisory Role: Lilly; Financial Interests, Advisory Role: Syros; Financial Interests, Advisory Board: Bridge Medicines; Financial Interests, Advisory Board: Earli; Financial Interests, Advisory Board: Harpoon Therapeutics. All other authors have declared no conflicts of interest.
Invited Discussant 3O and 1800O
- Jan Korbel (Heidelberg, Germany)