Step-by-step development of human T-cell vaccination
Besides preclinical testing, the development of novel treatments requires multiple small scale clinical phase I trials to elucidate toxicity and biological effects in humans. The pharmaceutical industry has the aim to rapidly upscale towards phase II / III clinical trials, in order to proof clinical efficacy. However, since most phase I trials provide results that represent only partial progress, the applied experimental treatments require further optimization. Thus, the majority of phase I studies re-direct research back to further preclinical studies. Thus, progress relies on an important loop “from bench to bedside and back to bench”. Our program for the development of human T-cell vaccination has the aim to optimize vaccine formulations such that they induce robust T-cell activation in melanoma patients. The vaccines are based on tumor antigenic peptides, to which we add various immunological adjuvants. Incomplete Freund's Adjuvant (IFA) was superior to various other adjuvants including ligands for Toll-like receptor-2 and -4 (TLR2 and TLR4). To optimize IFA based vaccines, we added bacterial-type CpG oligodeoxynucleotides known to trigger TLR9. Nearly all patients tested had strong in vivo proliferation of peptide specific T-cells, reaching ~10 fold higher T-cell frequencies than vaccination with peptide in IFA (without CpG), and 100-1'000 fold higher than with most other synthetic vaccines (e.g. with proteins, DNA, RNA, or recombinant viruses). The enhanced T-cell population consisted primarily of effector cells, with cytokine production and killing that was comparable to T-cells specific for persistent viruses (e.g. CMV and EBV).
T-cells primed by vaccination versus endogenous tumor antigen
Our studies revealed that weakly active T-cell vaccines primarily amplify immune responses that have been initiated (“primed”) spontaneously by tumor derived antigen. In contrast, the more powerful T-cell vaccine with CpG and IFA can also prime de novo T-cell responses. Our results show that vaccines need to be optimized towards selective activation of T-cells with highly specific TCRs. Furthermore, vaccine antigens may need to be targeted to particular anatomical sites, and to dendritic cells, which may enhance the selectivity of immune cell activation.
Immune escape and regulation in the tumor microenvironment
Tumor cells can escape from immune attack, e.g. through downregulation of antigen or MHC expression. Fortunately, the majority of melanoma patients bear tumors that remain positive for these critical molecules, even during progressive disease. However, in the tumor microenvironment there are further mechanisms interfering with T-cell immunity, for example through proteases, cytokines or immune regulatory cells. While animal models revealed basic functions, the responsible mechanisms in humans remain poorly understood. A major challenge is to establish the clinical settings, and the laboratory methods, allowing investigation of the human tumor microenvironment in detail, in vivo or directly ex vivo, avoiding artifacts introduced by in vitro culture systems.
Future treatments will rely on drugs that can overcome negative immune regulatory mechanisms in the tumor microenvironment. However, progress will also depend on vaccines that induce T-cell responses which are strong and systemic. Most promising are combination therapies. Future clinical studies require multiple drugs, and depend on productive collaboration between academia and industry.