Immunotherapies for ALK-driven cancers

One major research interest has been to study the mechanisms and pathways of tumor formation activated by the ALK oncogene, as well as the development of innovative therapies for AK-positive cancers, such as an ALK-specific cancer immunotherapy. Chiarle’s group has developed mouse models for both ALK-rearranged lymphoma and lung carcinoma to study the molecular pathogenesis of ALK-driven tumors. Recently, the group has developed an ALK vaccine that instructs the immune system to recognize and eliminate ALK-positive lymphoma and lung cancer cells. Additional areas of interest involve the study of the biological mechanisms of chromosomal translocation formation that initiate tumor formation. ALK-TKIs have produced impressive results in ALK-driven cancer. Unfortunately, such therapies have setbacks associated with the development of TKI resistance. Acquired resistance is commonly mediated by secondary mutations in the ALK kinase domain, bypass track activation, and other mechanisms. In this scenario, tumors are almost never fully eradicated by ALK inhibitors, and most patients eventually relapse being left without other valuable therapeutic options. We are currently implementing innovative ALK-specific immunotherapies (Figure 1) because the ALK protein has several features suitable for a tumor onco-antigen for cancer immunotherapy. ALK is expressed almost exclusively by tumor cells and is naturally immunogenic in humans. Patients with ALK-rearranged lymphoma and lung cancer spontaneously develop a natural immune response against ALK. Importantly, ALK is a potent driver oncogene required for tumor survival and growth, which minimizes the chances of escape of ALK negative tumor cells. We developed an ALK vaccine that generates strong and specific immune responses against tumors cells that express ALK as an oncogenic driver in a pre-clinical setting. We are now translating our results into the clinic. We are designing a Phase I clinical trial to combine ALK TKIs with an ALK vaccine based on the human ALK immunogenic peptides that we recently discovered and published. ALK vaccine is not effective in neuroblastoma (NB), therefore we are also developing ALK-specific chimeric antigen receptor (CAR) T cells to target tumors that express ALK on their surface, such as neuroblastoma. We have already generated and validated ALK-specific CAR T cells in pre-clinical models of neuroblastoma. We tested in vitro and in vivo the anti-tumor activity of hALK.CAR-Ts. We have cell lines or PDX models of NB to establish a biomarker that predicts therapeutic response and test the combination with ALK TKIs. We are implementing a Phase I clinical trial to treat neuroblastoma with a combination of hALK.CAR-Ts and ALK TKIs. Lastly, we are generating T cell receptor (TCR)-engineered T cells (TCR-T) against ALK instead of a vaccine. TCRs are naturally developed for sensitive antigen detection and can recognize epitopes at far lower concentrations than required for CAR-T activation. In addition, TCR-T cells can be exploited to attack antigens not expressed on the cell membrane, as EML4-ALK in ALK+ NSCLC. The generation of such cells will be a powerful tool used to eradicate ALK positive lung cancer cells and form the foundation of a TCR-T cell based clinical trial for patients with TKI-resistant ALK positive NSCLC.