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.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
3R01FD003452-02S1
Application #
7806244
Study Section
Special Emphasis Panel (ZFD1-OPD-L (01))
Program Officer
Needleman, Katherine
Project Start
2007-12-15
Project End
2009-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
2
Fiscal Year
2009
Total Cost
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612