Abstract PL07-02: The Renaissance of immunotherapy.
Authors: Eggermont Alexander M. Marie 
Published: August 2014

Abstract
Bringing down the walls of defense
The recent results of clinical trials with various anti-PD-1/PDL-1 monoclonal antibodies have converted many non-believers into believers of the enormous potential of immunomodulatory agents to gain control over some, if not many, solid tumors. Tackling immune suppression, seems to be a much more powerful intervention than short-lived immune-activating strategies and the current axioma of "inhibiting the inhibitor" and "breaking tolerance" appears to be a particularly powerful approach.
This was first demonstrated by the success of anti-CTLA4 molecules which “prevent the downregulation of CTL activity and/or reawaken immuneresponses that have gone silent.” The focus these days is very much on anti-PD1 and anti-PDL1 monoclonal antibodies that can prevent the downregulation of CTL activity at the tumor site because of PDL1 expression on tumor cells. Taking down very effective walls of defense is essential to give immune-therapeutic strategies a chance. Immune-stimulation alone with T-cell agonists or cytokines or vaccines is rather ineffective when defense mechnisms are intact centrally (lymph nodes: mostly CTLA4) and peripherally (tumor site: mostly PDL1). Moreover anti-CTLA4 and anti-PD1/PDL1 can synergize in boosting an effective immuneresponse leading to long lasting responses in high percentages of patients. The concept of a clinical cure emerges, as chronic control of metastatic disease is an emerging reality in melanoma, with immuno-combos. It is clear that checkpoint inhibitors open the door for the effective use of agonists, such as OX40, 4BB-1 and CD137 and for synergy with cytokines such as IL2 and IFN.
Key role of the immune system in various combination approaches
The immune system is the key-component of long term responses, not only in immunotherapeutic approaches. There is an increasing body of evidence that patients with long term responses or “clinical cure” conditions after chemotherapy or targeted-agent therapies depend on immunogenic cell death mechanisms, (re)activation of the immune system and the presence of prominent immune-infiltrates in residual tumor lesions.
Chemotherapeutics and targeted agents can lead to immunogenic or immune-tolerizing cell death, the first being associated with prolonged responses and control or even cure, the latter being associated with failure and death. Examples for immunogenic chemotherapeutics are anthracyclines, oxaliplatine, ionizing radiation and cyclophosphamide, whereas other chemotherapeutics (cisplatinum, mitomycin C, etoposide) have been found to induce unresponsiveness.
Therapeutics that cause immunogenic cell death
The molecular cues underlying this immunogenic cell death have been partly unveiled. Cell demise should be accompanied by an ER stress response which promotes calreticuline exposure and phagocytosis of dead cells by phagocytes. Next, autophagy is mandatory for ATP release and inflammatory monocytes to become dendritic cells (DC) priming T cell responses. Finally, HMGB1 release from the nucleus is indispensable to engage TLR4 on DC to accelerate the processing and antigen presentation to T lymphocytes By eliciting anticancer effector and memory T cells, immunogenic cell death contributes to the success of chemotherapy.Immunological off target effects have also been described for targeted agents and radiation therapy.
Conclusions
Clinical cures and eventually possibly a complete cancer cure becomes possible if we respect one basic principle: successful therapies require the induction / re-induction of anticancer immune responses. Renaissance is here.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL07-02.
Citation Format: Alexander M. Marie Eggermont. The Renaissance of immunotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL07-02.