Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) expressed during development in the nervous system. Aberrant expression of ALK drives several tumor malignancies. About 3-7% of non-small cell lung cancers (NSCLC) harbor ALK rearrangements. Treatment with the Tyrosine Kinase inhibitor (TKI) crizotinib results in a high objective rate response (ORR) of ∼60%, but median progression-free survival (mPFS) is only 8-10 months, owing to the rapid emergence of acquired drug resistance. Alectinib and ceritinib, a second generation of TKIs developed to overcome crizotinib resistance, induce a transient response followed by tumor relapses. Currently, there are at least 7 additional ALK TKIs in clinical development. Emergence of mechanisms of resistance to the new TKI is expected. Thus, innovative therapeutic approaches are needed to complement the partial success obtained by TKIs in ALK-positive NSCLC patients.
Three properties make of ALK a rather unique shared antigen: 1) ALK is a driver oncogene that is expressed in all the tumoral cells; 2) ALK is not expressed by normal cells with only marginal expression in few cells in the nervous system of adults, an immuneprivileged tissue, anticipating limited if any autoimmune side effects by an ALK-specific immunotherapy; 3) ALK is immunogenic in humans because ALK-specific antibodies and T cell responses are detected in ALK-positive lymphoma and lung cancer patients. As an additional advantage, the availability of ALK TKI to reduce tumor might facilitate immunotherapeutic approaches. Therefore, we aim to develop a strategy of vaccination in human patients to treat ALK-positive tumors in combination with TKIs and/or immunocheckpoints blockade.
We recently developed an ALK vaccine based on a DNA plasmid that generates an efficacious anti-ALK immune response in pre-clinical mouse models. This vaccine potentiates the effects of ALK TKI and can be combined with immune checkpoint blockade therapy. However, a consistent theme in human DNA vaccine trials has been their suboptimal immunogenicity when compared with protein-based vaccine approaches. To move towards a peptide-based vaccine, we sought to identify antigenic peptides responsible for these immune responses by in vitro screening with ALK overlapping peptides in splenocytes from ALK vaccinated mice and by MHC-I binding predictive algorithms. Four peptides induced IFN-γ production in splenocytes and one of these peptides contained a predicted CD8+ T-cell epitope. To validate these results in vivo, mice were vaccinated with these peptides. The peptide containing the predicted CD8+ 9mer was confirmed to induce CD8+ T-cell responses while the others induced CD4+ T-cell responses. To increase immunogenicity, peptides were modified with an amphiphilic tail. As we recently showed, this conjugation promotes binding to endogenous albumin, increasing lymph node accumulation and T-cell priming. In prophylactic experiments, mice vaccinated with the CD8+ T-cell epitope, but not the CD4+ T-cell epitopes, almost completely rejected ALK-expressing lung orthotropic tumors. To validate the efficacy of the vaccine in a therapeutic protocol, EML4-ALK transgenic mice that spontaneously develop ALK-positive lung tumors were vaccinated with a combination of these peptides. The vaccine significantly delayed the progression of primary lung tumors. We propose that a peptide-based ALK vaccine, combined with ALK TKI treatment and/or immune checkpoint blockade therapy, could represent a novel therapeutic option for ALK-positive lung cancer patients. A Phase I clinical trial with a peptide-based ALK vaccine in NSCLC patients is currently under preparation.
Citation Format: Rafael B. Blasco. Development of an ALK vaccine to treat ALK-rearranged non-small cell lung cancers [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A021.
- ©2016 American Association for Cancer Research.