Lung cancer is the leading cause of cancer death in the United States and is responsible for more deaths each year than breast, prostate, colon, hepatic, renal and skin cancers combined. Viewed in economic terms, in the United States, the value of life lost from lung cancer deaths in the year 2000 was more than $240 billion, which is estimated to rise to more than $433 billion in 2020. Because of the immense health care and economic burden imposed by lung cancer, new therapy strategies that improve patient outcomes will lead to very a significant impact. Collaborators at Chesapeake PERL, Inc. (C-PERL) and UCLA (Laboratory of Leonard Rome) have identified and characterized a unique nanoparticle structure called a vault that is highly stable, and found ubiquitously in all higher eukaryotes. The vault shell is entirely composed of multiple copies of a single protein called Major Vault Protein (MVP). MVP can be readily engineered to permit attachment of other agents, including promising cancer therapeutics like the chemokine CCL21. CCL21 is a lymphoid chemokine that is chemoattractant for mature dendritic cells (DCs), and naive and memory T cells. Preclinical studies in a lung cancer animal model have demonstrated that intratumoral administration of CCL21 gene-modified dendritic cells led to tumor eradication. Vaults have been expressed at Chesapeake PERL, Inc. (C-PERL) to very high levels using the PERLXpress protein expression platform. The unique and powerful system uses recombinant baculovirus expression in whole insects in an automated platform to generate high protein yields cost effectively. MVP and CCL21 (fused to a vault packaging peptide called INT) are readily expressed and correctly assembled to form CCL21-Vault nanoparticles. The particle has been shown to slowly release its chemokine payload over several days. Hundreds of milligrams of highly purified CCL21-Vaults can be readily prepared and stably stored in a lyophilized state for future therapeutic evaluation and testing. Continued development proposed in this Phase II application will support advanced development, pre- clinical safety evaluation including toxicology, efficacy, and formulation, leading to IND preparation to support future GCMP product manufacture. Intratumoral administration of recombinant CCL21-vaults derived from baculovirus infection of whole insects will be tested in a preclinical animal model for destruction of tumors. The CCL21-Vault is proposed to circumvent autologous DC preparation, minimize batch to batch variability and allow for comparability and standardization so that the particle can be used as an off-the-shelf reagent for advanced non-small cell lung cancer (NSCLC).
This project is relevant to treatment of common causes of death and disability due to lung cancer. The research will support continued development of a candidate therapy using a recombinant version of naturally occurring human vault protein in combination with CCL21 antitumor agent. The combination technologies may result in a drug that targets lung cancer, demonstrating a large scale, low cost, reproducible therapy. This is a potentially disruptive approach that can revolutionize the lung cancer field, and may be applied to other cancers.