Abstract
In situ tumor ablation techniques, like radiotherapy, cryo- and heat-based thermal ablation are successfully applied in oncology for local destruction of tumor masses. Although diverse in technology and mechanism of inducing cell death, ablative techniques share one key feature: they generate tumor debris which remains in situ. This tumor debris functions as an unbiased source of tumor antigens available to the immune system and has led to the concept of in situ cancer vaccination. Most studies, however, report generally modest tumor-directed immune responses following local tumor ablation as stand-alone treatment. Tumors have evolved mechanisms to create an immunosuppressive tumor microenvironment (TME), parts of which may admix with the antigen depot. Provision of immune stimuli, as well as approaches that counteract the immunosuppressive TME, have shown to be key to boost ablation-induced anti-tumor immunity. Recent advances in protein engineering have yielded novel multifunctional antibody formats. These multifunctional antibodies can provide a combination of distinct effector functions or allow for delivery of immunomodulators specifically to the relevant locations, thereby mitigating potential toxic side effects. This review provides an update on immune activation strategies that have been tested to act in concert with tumor debris to achieve in situ cancer vaccination. We further provide a rationale for multifunctional antibody formats to be applied together with in situ ablation to boost anti-tumor immunity for local and systemic tumor control.
Highlights
Vaccines have been extremely successful in preventing infectious diseases by training the immune system to recognize and destroy pathogens
An interesting novel approach is the in vivo loading and activation of dendritic cells (DCs) with tumor antigens released following in situ tumor ablation
DCs can further be activated by cell-cell contact and subsequent signaling via members of the immunoglobulin domaincontaining receptor family, especially the tumor necrosis factor (TNF) receptor family, such as CD40/CD40 ligand (CD40L) and CD27/CD70
Summary
Vaccines have been extremely successful in preventing infectious diseases by training the immune system to recognize and destroy pathogens. Immune responses induced by ablation as stand-alone treatment are documented, tend to be incapable of evoking robust sustainable anti-tumor immunity This is further evidenced by the scarce reports of spontaneous regression of untreated distant metastatic sites following ablation, the so-called ‘abscopal effect’ [3, 4]. Immunosuppressive TME like monoclonal antibodies (mAbs) against inhibitory immune checkpoints, inhibition of immunosuppressive cells like regulatory T cells (Treg) or myeloid derived suppressor cells (MDSC) or by scavenging anti-inflammatory cytokines, such as transforming growth factor beta (TGFb) Delivery of these immunomodulators to the relevant locations, i.e. the tumor and tumor dLNs, is often essential for enhancing anti-tumor specific immune responses following ablation. We postulate new combination strategies involving multifunctional antibody formats to be applied together with in situ ablation to boost the anti-tumor immunity for local and systemic tumor control
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