PROJET TBC
Treating Breast Cancer
Ce projet est porté par l’INSERM.
CONTEXT
Breast cancer is the most commonly diagnosed cancer in women world-wide, and metastatic breast cancer is the second leading cause of cancer-related deaths in American women. Breast cancer is classified into four distinct molecular subtypes based on the expression profile of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). In particular, triple-negative breast cancer (TNBC), characterized by the absence of ER, PR and no HER2 overexpression, is the most aggressive subtype of breast cancer. Also, HER2 positive defining a subgroup of breast tumors with aggressive behavior. Increased early screening, high-resolution imaging technology, and the design of effective chemotherapy, radiation, targeted, and immunotherapy sequences have extended patients’ lives significantly. However, the prognosis for patients with locally advanced and metastatic disease remains poor.
New therapies that promote anti-tumor immunity have been developed over the last decade. Most of these immunomodulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Although these therapies have led to unprecedented successes, only a minority of patients with cancer benefit from these treatments, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Harnessing innate immunity is emerging as a promising therapeutic approach to improving the efficacy of cancer treatment and overcoming resistance to current immunotherapies targeting T cells. In particular, harnessing NK cells in cancer patients presents the dual advantage of inducing the killing of tumor cells, but also of participating in a multicellular immune response against tumor cells. Correlations have been observed between patient clinical outcome and NK cell infiltration at the tumor bed or cytotoxicity of peripheral NK cells, in particular in breast cancer.
OBJECTIVES
We propose here to dissect the role of NK cells and type 1 innate lymphoid cells (ILC1s) in breast cancer with the aim of proposing innovative treatments in these diseases based on their manipulation using antibody-based drugs. This challenging project is conceived in order to define the heterogeneity of the NK cell and ILC1 compartments in luminal A/B and TBNC patients and to correlate with clinical outcomes. The results obtained in the frame of this project will also document, for the first time, the transcriptomic signature of NK cells and ILC1 in the context of HER2low/HER2+ metastatic breast cancer prior to and after Trastuzumab-Deruxtecan. In addition, we will evaluate the conception of a new treatment for HER2low/HER2+ breast tumor patients, which is a NK cell engager (NKCE) targeting HER2. NKCEs have the advantage of bringing NK cells and tumor cells together and are more potent than bi-specific mAbs currently used in clinics. We will also assess the potency of a NKCE in a tumor agnostic manner, as recent results have shown that trispecific antibodies that engage NK cells independently of a tumor antigen (TA) promote NK cell activation allowing in vivo tumor control, at some extent. As such, tumor agnostic NKCE are likely to be successful in others cancers beyond breast cancer.
RECENT PUBLICATIONS
1. Vivier, E, Rebuffet L, Narni-Mancinelli E, et al.; Natural Killer cell therapies. Nature. In press
2. Gauthier L, …, Vivier E. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nat Biotechnol. 2023 Sep;41(9):1296-1306.
3. Mosele F, …, André F. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023 Aug;29(8):2110-2120.
4. André F, et al.; Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773-1785.
5. Demaria O, et al.; Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant. Cell Rep Med. 2022 Oct 18;3(10):100783.
6. Narni-Mancinelli E, Vivier E. Advancing natural killer therapies against cancer. Cell. 2022 Apr 28;185(9):1451-1454.
7. Tolaney SM, …, André F. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020 Jun; 21(6): 763-775.
8. Gauthier L, …, Narni-Mancinelli E, Vivier E. Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity. Cell. 2019 Jun 13;177(7):1701-1713.e16.
9. Bertucci F, …, André F. Genomic characterization of metastatic breast cancers. Nature. 2019 May; 569(7757): 560-564.
10. André P, …, Narni-Mancinelli E, Cohen RB, Vivier E. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell. 2018 Dec 13;175(7):1731-1743.e13.