The long-term objective of this project is to develop a tumor-targeted T-Cell Receptor-Interleukin-2 (TCR-IL2) fusion protein, ALT-801, as an immunotherapeutic for treatment of melanoma and kidney cancers. The TCR portion of this fusion protein is specific for a peptide derived from the tumor associated protein p53 presented in the context of human leukocyte antigen. (HLA)-A2.1 This high affinity TCR is designed to guide the approved anti-cancer drug, interleukin-2 (IL-2), to the tumor site and minimize toxicity associated with IL-2 treatment. Based on the observed frequency of p53 overexpression in melanoma and kidney cancer of 20% to 50% and an estimated frequency of HLA-A2.1 of about 45%, use of ALT-801 as a treatment proposed here for a subpopulation of those with eventual mortality would likely target at most a few thousand annual U.S. cases. In a number of xenograft tumor models, the TCR-IL2 fusion protein inhibited the growth of primary tumors derived from human melanoma (and other human tumor cells) and exhibits significantly better antitumor activity than recombinant human IL-2 alone. The TCR-IL2 fusion protein also exhibits favorable pharmacokinetics and toxicity profiles in HLA-A2 transgenic mice. Based on these results, a chimeric form of the TCR-IL2 fusion (ALT-801) has been advanced as a clinical candidate for the treatment of cancer patients. For clinical development of ALT-801 described under this proposal, a clinical trial will be carried out in patients with locally advanced or metastatic malignancies to evaluate the safety, maximum-tolerated dose and pharmacokinetic profile of ALT-801. The safety profile and antitumor response of ALT-801 will be further assessed in an expanded cohort of patients with melanoma or kidney cancer. The following specific aims will be pursued: (1) conduct a Phase 1 dose-escalation trial in patients with progressive metastatic malignancies to examine the dose limiting toxicity, maximum tolerated dose, pharmacokinetics and antitumor response of treatment with ALT-801; (2) expand the number of patients with melanoma or kidney cancer in the maximum tolerated dose cohort to further assess safety and antitumor response of treatment with ALT- 801. Since p53 is overexpressed on around 50% of all tumors, demonstration of the safety and efficacy of ALT-801 in the treatment of melanoma and kidney cancer orphan indications could be of great benefit to the patient population experiencing many other types of rare cancers.
