A clinical trial is planned to evaluate the T-cell receptor gamma alternate reading frame protein (TARP), a novel protein that is expressed in patients with prostate cancer and breast cancer. TARP, a 58-amino acid protein, was identified using the NCBI Expressed Sequence Tags database. The mRNA is initiated in the J? 1 exon of the TCR ? and the protein expressed is initiated in an alternative reading frame than the TCR ? coding sequence. TARP is expressed both by normal and malignant prostate cancer tissue, with more than 90% of prostate cancer specimens positive for TARP expression. Two HLA A2 epitopes that produce cytolytic T-cell responses were determined. Epitope enhancement of the TARP peptides was performed to increase the level of immunity that could be generated with these peptides. Amino acid substitutions in the TARP27-35 peptide did not increase binding affintity and will be tested without modification, whereas amino acid substitutions in TARP29-37 did produce higher binding affinity peptides. For TARP29-37, Leu at position 9 were substituted with Val (TARP29-37-9V) and immunization with the peptide resulted in the production of T cells that recognize both the wild type and modified sequence. The study was planned as a comparison between peptide vaccine in adjuvant and pulsed on dendritic cells. The trial has not been initiated yet due to modifications in the dendritic cell maturation scheme under development by the Department of Transfusion Medicine, NIH. An alternative method of vaccination is also undergoing evaluation in patients with lung cancer. Through a CRADA collaboration with NewLink Genetics (Ames, IA), a clinical vaccine trial was initiated using allogeneic lung cancer cells that have been genetically altered with a Moloney murine retrovirus vector to express alpha (1,3) galactosyl transferase (alpha-GT) for patients with advanced non-small cell lung cancer. This trial has completed phase I testing and the phase II component has been initiated. Phase I has been completed with no serious or dose-limiting toxicity observed, and Phase II has accrued 19 patients to date. Approximately a quarter of patients have demonstrated prolonged stable disease of their lung cancers. A more than 8-fold increase in serum anti-alpha-gal antibody titers has been demonstrated in all patients (phase I), and a number of patients have shown interferon-gamma ELISPOT responses to the unmodified parental cell lines used in the vaccine. More importantly ELISPOT responses observed against non-small cell lung cancer cell lines not used as part of the vaccine suggest the ability of this approach to generate a more generalized anti-lung cancer immune response. Although peptide immunization with epitope-enhanced peptides reproducibly generates T cell responses in patients, tumor regression is infrequent. In addition, immune therapies in general produce long-lasting tumor regressions in only a small minority of patients. These observations suggest that there are immune mechanisms that prevent the induced immune response from producing tumor regression. A number of checkpoint controls in immune regulation can be targeted, including TGF-?, CTLA-4, PD1 and the CD4+, CD25+ T cell regulatory population. A clinical trial using an antibody that binds to and inhibits TGF-? is accruing patients at the highest dose level and will enter its phase II stage in patients with melanoma this year. Responses have been observed in patients with melanoma and toxicity has been minimal. We are currently evaluating the activity of MDX-010, a fully human antibody that binds to CTLA-4, to eliminate this checkpoint in regulation of T cell expansion. Responses have been observed in 4 of 16 patients with follicular lymphoma. The protocol has been modified to permit accrual of patients with other types of lymphoma, including other B cell lymphomas, T cell lymphoma, and Hodgkin's lymphoma. Three patients with Hodgkin's lymphoma have been treated. The antitumor activity of the CTLA-4 blockade was significantly enhanced in tumor-bearing animals by eliminating CD25+ cells using the PC61 antibody in studies conducted by Sutmuller. Our observation of an increase in this regulatory T cell population following MDX-010 administration provides an additoinal rationale for eliminating these cells to improve antitumor activity. It is likely that it will be necessary to eliminate multiple checkpoints in immune regulation for optimal antitumor activity. We are proposing to evaluate the combination of MDX-010 with daclizumab in an attempt to target CD25-expressing T regulatory cells. In a phase I trial (06-C-0200) we have been studying the safety, toxicity and antitumor activity of GC1008, a human monoclonal antibody targeting transforming growth factor-beta (TGF-) in patients with metastatic malignant melanoma and renal cell carcinoma. TGF-beta is a pleiotrophic cytokine that normally helps to maintains cellular homeostasis; however, in cancers TGF-beta promotes tumor cell proliferation, migration, metastasis, neoangiogenesis and suppressesion of the host antitumor immune response. Cohorts of patient were treated with GC1008 doses ranging from 0.3 to 15 mg/kg. No maximum tolerated dose was determined; however, extensive eruptive keratoacanthomas were observed in 2 patients and a squamous cell carcinoma of the skin in a third patient. There was one very good partial response in a patient with extensive cutaneous melanoma, two mixed responses were seen and two patients with stable disease were observed. This trial has been extended at the highest dose (15 mg/kg) to in an effort to getachieve a better estimate of the incidence of keratoacanthomas and other skin events associated with this agent. Future clinical studies are planned using GC1008 in combination with chemotherapy and antitumor vaccines in melanoma, breast and prostate cancer. Also in late stage regulatory review, is a first-in-human trial of recombinant human interleukin-15 (rhIL-15). Interleukin-15 (IL-15) is a powerful immunostimulatory cytokine with a broad range of biological activities that was co-discovered in the Metabolism Branch, NCI. In contrast to IL-2, IL-15 inhibits the activation-induced cell death (AICD) of T-cells and is not involved in the maintenance of CD4+CD25+ regulatory T-cells that act as inhibitory checkpoints on the immune response. IL-15 is involved in the proliferation, differentiation and activation of CD8+ T-cells and NK cells and the maintenance of long-term central memory CD8+ T-cells. In preclinical studies, vaccines expressing IL-15 induced long-lasting, high-avidity CD8+ cytotoxic T-lymphocyte (CTL) mediated immunity, whereas the immunity mediated by IL-2 expressing vaccines was short lived. IL-15 can overcome that lack of CD4+ T-help to induce both CD8+ CTL and humoral immune responses. IL-15 was shown to be highly active against a number of syngeneic mouse-tumor models and it is also effective in augmenting the activity of NK cells and CD8+ T-cells in rhesus macaques indicating that it may be active against human cancers. The National Cancer Institute has coordinated a program in the BDP that produced GMP grade recombinant human IL-15 (rhIL-15) for use in patients with metastatic melanoma and renal cell cancer in a phase I clinical trial to be run in the Metabolism Branch scheduled to begin in early 2009.
| O'Mahony, Deirdre; Morris, John C; Quinn, Cate et al. (2007) A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res 13:958-64 |
| Berzofsky, Jay A; Ahlers, Jeffrey D; Janik, John et al. (2004) Progress on new vaccine strategies against chronic viral infections. J Clin Invest 114:450-62 |
| Berzofsky, Jay A; Terabe, Masaki; Oh, SangKon et al. (2004) Progress on new vaccine strategies for the immunotherapy and prevention of cancer. J Clin Invest 113:1515-25 |
