Targeting bicarbonate transport as a “first-in-class” therapeutic strategy to promote CD8+ T cell fitness and enhance cancer immunotherapy

Project Information

BasicFit

Grant agreement ID: 101069459

DOI

10.3030/101069459

Project closed

EC signature date 27 June 2022

Start date 1 September 2022

End date 29 February 2024

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

VIB VZW
Belgium

Periodic Reporting for period 1 - BasicFit (Targeting bicarbonate transport as a “first-in-class” therapeutic strategy to promote CD8+ T cell fitness and enhance cancer immunotherapy)

Reporting period: 2022-09-01 to 2024-02-29

Summary of the context and overall objectives of the project

Although immunotherapies have revolutionized cancer treatment, many patients fail to benefit from them. In this scenario, the complex metabolic crosstalk between the different cells within the tumor microenvironment (TME) is pivotal in regulating immunosuppression and overall instructs resistance to current therapies. Particularly our work highlighted how acidity within the tumor microenvironment (TME) contributes to its immunosuppressive features and dampens anti-tumor immune cell functions in pancreatic ductal adenocarcinoma (PDAC). with this project, we identified SLC4A4 as a key bicarbonate transporter on cancer epithelial cells contributing to such highly acidic environment. Genetic inhibition of SLC4A4 mitigated tumor acidity and restored CD8+ T cell fitness. Moreover, combining SLC4A4 targeting with immunotherapy improved survival in a murine PDAC model. Based on this work and given the lack of specific pharmacological inhibitors of SLC4A4, with the contribution of this grant we generated and patented first-in-class blocking nanobodies targeting SLC4A4. The restricted expression of SLC4A4 to the epithelial compartment makes it an ideal target to tackle tumor acidosis without impairing the function of other cell populations within the TME. The overarching goal of this project is to bridge the gap between our fundamental research and its clinical application by developing first-in-class nanobody-based SLC4A4 blockers.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

in the frame of this PoC grant, we confirmed our preliminary results; further validated the molecular mechanism through which expression of SLC4A4 in pancreatic cancer cells instruct immunosuppression and expanded the application relevance of SLC4A4 targeting for cancer therapy.
particularly the obtained results resulted in 1 high impact scientific publication (Cappellesso et al Nat Cancer 2022), two patents (of which one composition of matter application EP21157705.1 and EP23172907.0) generation of preliminary results supporting further grant applications and interaction and collaboration with industrial partners.

Of particular relevance, after the publication of Cappellesso et al Nat Cancer 2022, our results stimulated VIB discovery science to sponsor the generation of first-in-class nanobody blockers targeting SLC4A4. Part of the ERC PoC activities contributed to validating these therapeutic candidates for cancer therapy

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

in the frame of this PoC grant, we achieved all set objectives.

first of all, thanks to the deep characterization of the molecular mechanism underlying SLC4A4-dependent tumor acidosis we were able to obtain a high-impact scientific publication (Cappellesso et.al. 2022) that defined and characterized a novel metabolic cross-talk linking cancer cell metabolism, acidosis, and immunosuppression.

to ensure the valorization of the ensured results we filed a patent covering SLC4A4 inhibition in the cancer setting in association with immunotherapy. particularly thanks to the work sponsored by this ERC PoC we were able to expand the field of application from PDAC to include NSCLC and glioblastoma.

these results stimulate the attention of institutional departments which further economically support the translation of our scientific results into a drug discovery program to develop therapeutic drug candidates. particularly VIB discovery science sponsored the generation and characterization of nanobody blockers specific for SLC4A4; and KULeuven granted a C3 translational grant (500k euros) to allow the characterization of the nanobody blockers. overall the performed science allows the filing of a "composition of matter" patent application where the generated nanobody blockers are IP protected for cancer treatment and in other diseases (relevance of this target has been reported in the context of type 2 diabetes mellitus, cystic fibrosis, ischaemic heart disease, for example).

at the current stage, we are seeking for a biopharma partner that would in-license the program for further clinical development towards IND filing, and are in negotiation and collaboration with other biotech and pharmaceutical companies investigating the potential use of our specific blockers in other disease indications outside of the cancer field.