Tackling the Achilles Heel of Immunotherapy: Validating imaging biomarkers and targeting the immunological niche of tumour hypoxia

Informations projet

HYPOXIMMUNO

N° de convention de subvention: 694812

DOI

10.3030/694812

Projet clôturé

Date de signature de la CE 30 Novembre 2016

Date de début 1 Decembre 2016

Date de fin 31 Mai 2023

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 499 399,00

Contribution de l’UE

€ 2 499 399,00

Coordonné par

UNIVERSITEIT MAASTRICHT
Netherlands

Periodic Reporting for period 4 - HYPOXIMMUNO (Tackling the Achilles Heel of Immunotherapy: Validating imaging biomarkers and targeting the immunological niche of tumour hypoxia)

Période du rapport: 2021-06-01 au 2023-05-31

Résumé du contexte et des objectifs généraux du projet

The absence of effective anticancer treatment, in combination with the steeply rising prevalence of cancer, underscores the urgent need for more specific and effective cancer therapies in combination with biomarkers to select the right patient for the right treatment. Overall, this is a typical project of convergence sciences sitting at the intersection of clinical sciences (WP4), biology (WP1-2) and technology (WP3).

Immune checkpoint inhibitors (ICIs), monoclonal antibodies relieving T-cells from their negative regulation, elicit robust anti-tumour immune responses in advance-staged cancer patients, however with only limited durable responses. Accumulating evidence suggests that oxygen deficiency (hypoxia) within tumours is an important phenomenon to suppress the anti-tumour immune response. Therefore, we hypothesised that targeting hypoxia may improve the efficacy of immunotherapy through lowering the tumour hypoxic fraction, using a next generation hypoxia-activated prodrug (HAPng). Only under severe hypoxic conditions, the HAPng leads to the generation of active metabolites to exert its cytotoxic effect as DNA crosslinker (https://youtu.be/1sidMh5ZF70). We hypothesized a beneficial therapeutic outcome of a trimodal therapy, more specifically the combination of immunotherapy (“pushing the accelerator” with L19-IL2 and “releasing the break” with checkpoint inhibitor (https://youtu.be/7ckZeWWyhts)) with HAPng. We have obtained experimental evidence that HAPng can increase the immunological visibility of tumours via an increase in immunogenic cell death (ICD). In addition, using the concept of HAPs, we will bring immunomodulators targeting TLR7/8 in these hypoxic areas in order to stimulate the activation of pro-inflammatory cytokines.

Another way to tackle hypoxic cells is to use radiotherapy with high linear energy transfer (LET) such as carbon ions. Compared to conventional photon radiotherapy, carbon ions will have a higher deposition of the actual radiation dose at the tumour site without being influenced by hypoxia. Experiments have been completed in collaboration with DKFZ (Heidelberg).
Furthermore, to establish an ideal individualized therapy, the identification of biomarkers of therapy efficacy is similarly important. Thus, it would be beneficial for patients as well as being cost-effective if the outcome of therapy could be predicted based on biomarker(s) assays to guide the most optimal treatment selection for each individual patient. We envision biomarker(s), preferably tri-dimensional, imaging-based and non-invasive such as radiomics approaches, as a powerful tool to maximize a therapeutic benefit for patients.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We have demonstrated that the synergistic effect of radiation is greater with immunocytokine then with checkpoint inhibitor and that combined immunotherapy is more efficient then one of the two single approaches. After completion of the phase 1 trial (NCT02086721), the ImmunoSABR phase 2 trial (https://www.immunosabr.info/) is currently recruiting patients. Within this trial, we investigate the Progression Free Survival after double or triple therapy compared to SOC in stage IV NSCLC patients (< 10 metastasis). >80 patients have been enrolled in this trial.
The HAP CP-506 has been investigated thoroughly as monotherapy in several tumour models showing a therapeutic efficacy independent of the baseline hypoxic fraction. Using knockout cell lines we were able to show that CP-506 activity depends on Homologous Recombination (HR) and Fanconi Anemia (FA) status. CP-506 is also capable of sensitizing tumours to irradiation, immunotherapy (immunocyokines or checkpoint inhibitors, see figure 1) and chemotherapy. Based on these data, the phase 1 (safety monotherapy NCT04954599) has been approved by the Medical Ethical Committees within The Netherlands and Belgium. Patient recruitment has started. In addition, we will also investigate the approach of bringing immunomodulators in hypoxic areas, by using new “HAP-immunomodulators”. The synthesis of these compounds is finalized (Montpellier) and biological activity has been evaluated.
We tested in collaboration with Heidelberg the combination of Carbon ion irradiation with different LET and immunocytokines. High LET irradiation had a therapeutic benefit compared to X-rays, which was further enhanced upon combination with immunocytokines. Preliminary results indicate involvement of CD8 cytotoxic T cells, NK cells and eosinophils. Investigations of the changed mutational landscape is currently under investigation.
Thanks to numerous advances in the field of radiomics image analysis (Lambin et al., Nat Rev Clin Oncol, 2017), we are making great progress in our ability to implement radiomics imaging biomarkers to improve patient selection. In parallel, there are multiple steps still requiring further rigorous attention and are currently under investigation. We have managed to generate validated hypoxia signatures on both CT and FDG-PET, with a radiomics approach. We found that the use of nitroglycerin (a repurposed vasodilating drug) patching to target hypoxia, did not result in improved outcome. We gathered and curated image data to validate currently published immunotherapy response CT signatures. There are key technological achievements such as the use of longitudinal cone beam CT data for radiomics analysis.

Dissemination and exploitation has been mainly through 1) PhD theses, 2) peer-reviewed scientific publications, 3) invited talks and collaborations with companies.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

A. Pre-clinical work (WP1-2)
- Further characterization of the DNA damage response to CP-506
- Identification of potential biomarkers of response to CP-506
- Testing the combination of CP-506 with standard-of-care treatments
- Evidence that removing the immunoresistant hypoxic areas will sensitize tumours to immunotherapy and reveal the molecular mechanism
- Test the therapeutic efficacy of fractionated high LET irradiation (RBE-adjusted dose) in combination with immunotherapy and reveal the molecular mechanism
- Test intratumoural clostridium as delivery system of immunotherapeutics (https://vimeo.com/251022032) a project for which we received a ERC PoC (CL-IO).

B. Radiomics as biomarker (WP2)
- A fully automated lung tumour segmentation algorithm, a project for which we received a second ERC PoC (AutoDistinct)
- A radiomics signature that can
1) detect lung cancer histologic subtype
2) accurately predict tumour oxygenation status
3) accurately evaluate immunotherapy response
4) predict patients likely to develop pneumonitis after immunotherapy.
5) to detect HRD preclinically.

C. Clinical trials (WP4)
Regarding ImmunoSABR (phase 1 completed, randomized phase 2 running: https://www.immunosabr.info/) we will:
- Investigate the combination radiotherapy and immunotherapy alone vs triple therapy (radiotherapy + Immunocytokine + checkpoint inhibitor)
- Use this information for the next trial adding an HAP (NCT04954599, METC obtained, patient recruitment started), including
1) tumour hypoxia based on CT radiomics
2) HRD radiomics signatures

Overall this project is very successful (> 50 papers, three patents, three clinical trials, three completed PhD theses, three ERC PoC and technology transfer activities) and is a perfect example of convergence sciences, integrating knowledge form clinical sciences, technology and biology.

Survival Curves