Trial Information

Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

Most current cancer treatment strategies involve the use of chemotherapeutic or biological
drugs that exhibit variable efficacy and considerable toxicity. The limitations are often
the result of the adverse side effects of the therapeutic drug on normal tissues. One
approach to control these effects is to target the therapy to the tumor site. Of the
identified tumor antigens, the human p53 tumor suppressor protein is overexpressed in a wide
range of human malignancies. p53 is an intracellular tumor suppressor protein that acts to
arrest the proliferation of cells. When mutated, it loses its ability to suppress abnormal
proliferation and exhibits a longer half-life than the wild-type protein, allowing for its
accumulation in tumors. In addition, p53 overexpression correlates with tumor transformation
and aggression and is associated with lower overall survival rates and resistance to
chemotherapeutic intervention in cancer patients. Therefore, p53 appears to be a marker for
a considerable number of human malignancies and represents a good target for
immunotherapeutics. However, p53 cannot be used as a target for antibodies because it is not
displayed independently on the cell surface. Instead, the p53 protein is processed
intracellularly into peptide fragments that are then displayed on the cell surface in the
context of MHC. These peptide/MHC complexes are recognized by T-cells via their T-cell
receptors (TCRs). Recently it has been confirmed that a p53 peptide fragment is
significantly elevated in a wide range of human tumor tissues, particularly in melanoma,
renal, lung, breast, colorectal, and osteosarcoma cancers. As a result, the feasibility of
using soluble TCRs to target therapies against tumor cells that overexpress p53 is being
investigated.

Interleukin-2 (IL-2) is a well-characterized growth factor for immune effector cells which
play critical roles in tumor control and rejection. As a result, recombinant human IL-2
(e.g., Proleukin®, Chiron Novartis) has been approved for treatment of metastatic melanoma
and renal cell carcinoma. IL-2 treatment provides significant benefit to a subset of
patients with some maintaining durable responses for over ten years post-treatment.
However, the major drawbacks of IL-2 therapy are its limited half-life and severe systemic
toxicity. Hence, the use of high dose IL-2 is limited to specialized programs with
experienced personnel, and it is generally offered to patients who are responsive and have
excellent organ function. The low dose IL-2 treatment, while less toxic and more convenient,
produces lower response rates and appears to be less effective in treating metastatic
tumors. Thus, there is a critical need for innovative strategies that enhance the effects
of IL-2 or reduce its toxicity without compromising clinical benefit. Targeted approaches
to concentrate therapeutic cytokines, such as IL-2, at the tumor sites that express p53
could provide considerable advantages over current treatment.

The study drug, ALT-801, is a biologic compound composed of interleukin-2 (IL-2) genetically
fused to a humanized soluble T-cell receptor directed against the p53-derived peptides
expressed on tumor cells. This study is to evaluate whether directing IL-2 activity using
ALT-801 to the patient's tumor sites that overexpress p53 results in clinical benefits if
the ALT-801 treatment is given with cisplatin.

Platinum-based analogues including cisplatin, alone or in combination with other
chemotherapies, have been shown to be active in patients with metastatic melanoma.
Additionally, it is known that cisplatin, an alkylating agent known to inhibit DNA synthesis
of dividing cells, triggers increased intracellular level of p53. The synergistic effects of
cisplatin and ALT-801 treatment may induce cisplatin-mediated increases in p53 peptide
display on the tumors and subsequently enhance tumor targeting of ALT-801.