CAR T cell therapies have proven successful in the clinic, but their broad application is still facing significant challenges due to the elaborate and expensive engineering and manufacturing of cells. Sanofi has developed a new technology that allows the generation of CAR T cells directly in vivo. The technology uses mRNA, formulated in LNPs that are specifically targeted to circulating T cells to transiently express CARs on the surface.

CAR T cells can proliferate and persist in patients for several years. However, this remarkable feature comes with a drawback: once administered, it is challenging to control their activity. To address this limitation, we have engineered molecular switches, enabling regulation of CAR T cell activity with small molecule drugs. As an alternative strategy, we developed AvidCARs, which enable both combinatorial antigen recognition and drug-mediated control of CAR T cell function.

The Notch-signaling ligand JAG1 is a key oncogene involved in aggressive solid tumors correlated with poor clinical prognosis. Here we report novel anti-JAG1 scFvs that specifically recognize JAG1 in the Ab format and show that one molecule enables CAR T cells to specifically recognize JAG1-expressing cells promoting their killing. These findings suggest this new anti-JAG1 scFv might be a good candidate for the development of cell therapies targeting JAG1-positive tumors. The talk will cover:

• Novel specific anti-JAG1 scFv identied from phage display libraries
• Developed anti-JAG1 Abs specifically recognizing cellular JAG1
• JAG1 CAR constructs carrying new specific anti-JAG1 scFv fragments
• Engineered anti-JAG1 CAR T cells activated upon JAG1 recognition
• Anti-JAG1 primary T cells specifically and effectively kill JAG1-positive cells

This talk will present the innovative SYNCAR technology which leverages engineered IL-2/IL-2Rß orthogonal pairs to selectively enhance the anti-tumor efficacy of CAR T cells, addressing challenges faced in both liquid and solid tumor models.

Tedopi is a tumor-specific activating immunotherapy based on highly-selected and optimized tumor neoepitopes. This subcutaneous cancer vaccine activates and expands tumor-specific CD8 T lymphocytes both in periphery and in tissue (e.g., lung) capable of killing tumor cells. We recently reported positive clinical efficacy of Tedopi versus chemotherapy in a randomized Phase III trial in Non-Small Cell Lung Cancer in patients with secondary resistance after failure of checkpoint inhibitors [Anti PD-(L) 1] with:

• Significantly better survival: 44% overall survival at 1-year, versus 27% with chemotherapy
• Significantly better safety profile: 3-fold less severe Grade 3-5 adverse events
• Significantly better quality of life based on several patient-related outcomes

I will discuss the newer checkpoint inhibitors as well as current data from different vaccine platforms studies available to date, and give an update on the melanoma phase 2 data from our collaboration with Moderna.

This presentation will discuss the biology of the CD47-SIRPα myeloid immune checkpoint and considerations for its therapeutic targeting in combination with, in particular, tumor-targeting antibodies. Furthermore, the preclinical development of BYON4228, a potentially best-in-class agent in the field, will be reported.

ATOR-4066 is a novel bispecific antibody, built in the RUBY format within Alligator Bioscience’s Neo-X-Prime concept, targeting the tumor-associated antigen CEA (CEACAM5) on tumor cells and CD40 on myeloid cells. ATOR-4066 is designed to induce efficient CEA conditional activation of myeloid cells, as well as to drive uptake of neoantigen-containing tumor-derived material and subsequent cross-priming of tumor-specific T cells. This talk will describe the data-driven design and engineering of ATOR-4066 and its optimized properties.

We will provide an update on Numab’s immunotherapy approach, which utilizes an affinity-balanced trispecific construct targeting PD-L1/4-1BB/HSA. Also other multi-specific programs for which affinity tuning is essential will be presented.

We utilize a novel gene delivery approach using a retargeted adenoviral vector as a novel anti-cancer immunotherapy. The adenoviral vector is targeted to specific cellular receptors overexpressed on tumor cells using binding proteins. Upon transduction of tumor cells, we show that the local production of IgA antibodies and a checkpoint inhibitor leads to efficient tumor cell killing in a microfluidic all-human tumor-on-a-chip system by neutrophils through antibody-dependent cellular cytotoxicity, and by macrophages through antibody-dependent cellular phagocytosis.

This presentation highlights the preclinical discovery of ARX622, a site-specific HER2-targeted TLR7 agonist ADC with stable conjugation, efficacy in large established tumor models, and a wide therapeutic index based on preclinical exposure data.