Targeting activity of a TCR/IL-2 fusion protein against established tumors

Abstract

We have previously reported that a single-chain T cell receptor/IL-2 fusion protein (scTCR-IL2) exhibits potent targeted antitumor activity in nude mice bearing human tumor xenografts that display cognate peptide/HLA complexes. In this study, we further explore the mechanism of action of this molecule. We compared the biological activities of c264scTCR-IL2, a scTCR-IL2 protein recognizing the aa264-272 peptide of human p53, with that of MART-1scTCR-IL2, which recognizes the MART-1 melanoma antigen (aa27-35). In vitro studies showed that c264scTCR-IL2 and MART-1scTCR-IL2 were equivalent in their ability to bind cell-surface IL-2 receptors and stimulate NK cell responses. In mice, MART-1scTCR-IL2 was found to have a twofold longer serum half-life than c264scTCR-IL2. However, despite its shorter serum half-life, c264scTCR-IL2 showed significantly better antitumor activity than MART-1scTCR-IL2 against p53(+)/HLA-A2(+) tumor xenografts. The more potent antitumor activity of c264scTCR-IL2 correlated with an enhanced capacity to promote NK cell infiltration into tumors. Similar differences in antigen-dependent tumor infiltration were observed with activated splenocytes pre-treated in vitro with c264scTCR-IL2 or MART-1scTCR-IL2 and then transferred into p53(+)/HLA-A2(+) tumor bearing recipients. The data support a model where c264scTCR-IL2 activates immune cells to express IL-2 receptors. Following stable interactions with cell-surface IL-2 receptors, c264scTCR-IL2 fusion molecule enhances the trafficking of immune cells to tumors displaying target peptide/HLA complexes where the immune cells mediate antitumor effects. Thus, this type of fusion molecule could be used directly as a targeted immunotherapeutic or in adoptive cell transfer approaches to activate and improve the anti-cancer activities of immune cells by providing them with pre-selected antigen recognition capability.

Alternative therapies in patients with non-muscle invasive bladder cancer

“…Among these, vesigenurtacel-L is made of an allogeneic cell line, has been selected for high expression of bladder tumor antigens to induce immune response over CD+ cytotoxic t-lymphocytes. [71] Despite lack of any clinical data , a phase 1 study has revealed an increased rate of tumor infiltrating lymphocytes (60% vs. 16%) after intradermal vaccine injections combined with BCG treatment. [72] Meanwhile, ALT-801 is a fusion molecule between IL-2 and t-cell receptor that enhances immune response by displaying target peptide/HLA complexes.…”

“…[72] Meanwhile, ALT-801 is a fusion molecule between IL-2 and t-cell receptor that enhances immune response by displaying target peptide/HLA complexes. [73] The ongoing phase Ib/II study (NCT01625260) basically evaluates systemic administration of ALT-801 with GEM. The primary end point is clinical efficacy which will be evaluated at 13 weeks; whereas duration of response, progression-free and event-free survival rates are to be evaluated in up to 3 years.…”

Molecular biology and targeted therapies for urothelial carcinoma

“…ALT-801 is a T-cell receptor/interleukin-2 fusion protein that activates natural killer and CD4+ lymphocytes to secrete IFNgamma, as well as CD8+ lymphocytes, resulting in a sustained immunological memory against UC cells in pre-clinical models [108]. ALT-801 is currently under evaluation in combination with CG in mUC in a phase I/II trial (NCT01326871).…”

Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review

“…This fusion protein activates the IL-2 receptor in infiltrating T cells promoting T cell expansion and differentiation in effector T cells, thereby promoting anti-tumoral activity [159,160]. In addition, preclinical studies demonstrated an antitumor activity of ALT-801 against p53+/HLA-A*0201 tumors likely mediated by natural killer cell tumor infiltration [161,162]. Regarding this, Fishman et al [163] conducted an open label, dose escalation, phase I clinical trial to evaluate the efficacy, toxicity, pharmacokinetics and immunological effects of ALT-801 in 26 p53+/HLA-A*0201 patients with progressive metastatic malignancies including bladder cancer (therapeutic regimens detailed in Table 1).…”