Program in Immunology and Bio-immunotherapy of Cancer (PIBIC)
Heads: Giorgio Parmiani and Paolo Dellabona
The immune system plays a critical role in protection against malignancy. Loss of immunity is often associated with an increased risk of cancer; conversely, a strong immune response may be protective, and this can be exploited for therapeutic purposes. The work of recent years indicates that T cell response is associated with prognosis in several histologically different human tumors, with the presence of Tregs and T effector cells being predictive of worse and good prognosis, respectively. These findings constitute one of the strongest evidence that the immune system contributes to the control of tumor growth in humans.
Despite the limited clinical outcome of the last 10 years, the interest for tumor immunotherapy is maintained high thanks to the following evidences:
a) Most of the rare (10%) tumor responses (partial or complete) are durable;
b) The progress made in the knowledge of the biology of immune cells can be rationally exploited to improve their clinical efficacy;
c) Recent clinical trials have reported a better survival in melanoma, breast and lung cancer patients receiving multi-antigen vaccines; moreover, the first statistically significant positive results in terms of overall survival of a phase III randomized trial in metastatic prostate cancer vaccinated with a prostate-loaded dendritic cells (Provenge study) have been presented;
d) Several molecular mechanisms of immune deviation and tumor escape have been elucidated and they can now be, at least partially, counteracted by appropriate interventions on the immune system and/or on tumor cells;
e) Components of the tumor microenvironment can affect anti-tumor immunity. Indeed, biological or genetic strategies that target tumor vascular endothelium or tumor-associated macrophages, respectively, induce therapeutic responses in mouse models, prompting the investigation of possible synergies with immunotherapy.
Thus, many recent pre-clinical and clinical studies, to which also research groups of the San Raffaele Scientific Institute have significantly contributed, have generated relevant new information that can now be incorporated in designing potentially improved active (vaccination) and/or adoptive immunotherapy trials.
In order to overcome the biological hurdles that prevent a more efficient clinical responses, it is important not only to modify the immunotherapy strategies, but also to redefine the endpoints of clinical trials that will assess their efficacy in patients undergoing immunotherapy, such as considering clinically predictive biomarkers, the correlation of immune and clinical response and the patients survival rather than tumor response.
The major objectives of the PIBIC are twofold: i. a deeper understanding of the mechanisms underlying the tumor/immune system interactions; and ii. the provision of new immunotherapy strategies that are rationally designed to increase significantly the therapeutic efficacy of the current ones. The research performed in the PIBIC will be guided by the “bench-to bedside-to bench” principle, which defines the idea that translational research carries results not only from bench to bedside, but also in the reverse polarity, considering that patients unexpected responses in well designed clinical trials are valuable human experiments, and can stimulate new hypotheses that may help improving the outcome of subsequent studies.