Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies

Abstract

Purpose: ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies.

Experimental design: p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose.

Results: Four, 16, and 6 patients were treated at the 0.015, 0.04, and 0.08 mg/kg cohorts, respectively. Two dose-limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum IFN-γ but not TNF-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions.

Conclusion: This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunologic changes of potential antitumor relevance.

Trial registration: ClinicalTrials.gov NCT00496860.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest: B. Y. Huang, S. Tang, P. R. Rhode and H. C. Wong are employees of and equity owners in Altor BioScience Corp.; J. Weber is a paid consultant of Altor Bioscience Corp.

©2011 AACR.

Figures

Figure 1

Detection of p53 (aa264-272)/HLA-A*0201 complexes on formalin-fixed paraffin-embedded tumor specimens. A, IHC staining of tumor specimens from patients with melanoma and renal cell carcinoma (RCC) using p53 (aa 264-272)/HLA-A*0201-specific (264scTCR) and control (CVMscTCR) reagents. B, positive IHC staining of other tumor histologies using the p53 (aa 264-272)/HLA-A*0201-specific reagent. The staining of tumor cells was assessed as 3+ (4006, 1011, 1006, 2004) or 2+ (2001, 2002) versus 1+ for normal cells in these specimens.

Figure 2

Tumor assessment by RECIST of subjects following a single course of ALT-801 treatment. For each subject, the number of ALT-801 doses actually administered of the planned 8 doses is shown in parentheses. Subjects with new lesions on assessment or who withdrew from the study prior to assessment were labeled as progressors.

Figure 3

Immunogenicity analysis. Serum anti-ALT-801 Ab levels were determined in subjects at 4, 7 and 11 weeks after the initiation of treatment with 0.015 (closed squares), 0.04 (open triangles) or 0.08 mg/kg (closed triangles) ALT-801. Values expressed as median ± interquartile range.

Figure 4

Effect of ALT-801 on patients immune cell distribution and response. A, blood lymphocyte levels during treatment course in patients receiving 8 doses of 0.04 mg/kg ALT-801. B, serum IFN-γ levels following dose 1 (closed squares), 4 (open triangles), 5 (closed triangles) and 8 (open diamonds) of ALT-801 given at 0.015 (left), 0.04 (top) or 0.08 (right) mg/kg. C, cellular immune responses determined by IFN-γ ELISPOT analysis of patients following treatment with ALT-801 given at 0.015 (left), 0.04 (top) or 0.08 (right) mg/kg. Induction of IFN-γ positive cells in human PBMCs was determined after overnight with medium alone (closed squares) or medium containing ALT-801 (open triangles), p53-positive A375 tumor cells (closed triangles) or ALT-801 + A375 tumor cells (open diamonds). Values expressed as mean ± standard error of the mean. * P