DCs Flashcards
<p>Why is DC therapy not suitablefor cancer tx on its own?</p>
<ul> <li>not effective at clearing large masses/solid "reservoirs" of tumour cells</li> <li>immune system not designed to breakdown large masses of tissue</li> <li>DC therapy better for loose, disseminated, "rare" events</li></ul>
<p>Benefits of DC therapy in cancer tx</p>
<ul> <li>good at eliminating "rare events" <ul> <li>picking up loose, disseminated cells missed by conventional Sx, chemo or radiotherapy</li> <li>exemplified by ability to clear all infected cells following a non-latency viral infection</li> </ul> </li> <li>can target heterogeneous tumours with <ul> <li>multiple antigenic targets</li> <li>"epitope spreading"</li> </ul> </li> <li>low toxicity</li></ul>
<p>Challenges for DC immunotherapy</p>
<p><strong>tumour-associated immunosuppression</strong></p>
<ul> <li>cancer does not present "danger" signals (e.g. TLR ligands) <ul> <li>needed to drive co-stimulation expression</li> </ul> </li> <li>cancer cells produce suppressive/tolerogenic factors (e.g. IL-10, TGF-B) <ul> <li>DC dysfunction</li> <li>drives DCs to become tolerogenic</li> </ul> </li> <li>cancer-induced expansion and hyperactivation of Tregs + MDSC + suppressive pDCs <ul> <li>due to IL-10/TGF-B secretion</li> <li>COX2/PGE-2 pathway</li> <li>CCL22, CCL28 - attracts Tregs via (CCR4, CCR10)</li> <li>CXCL12, CXCR4 - attracts MDSCs + suppressive pDCs</li> </ul> </li></ul>
<p>Desired features of DCs for cancer tx (5)</p>
<ul> <li>high stimulatory function <ul> <li>high MHCI/II+ co-stim (signal 1, 2)</li> </ul> </li> <li>induction of CTL + Th1 <ul> <li>high IL-12 (signal 3)</li> </ul> </li> <li>migration for regional LNs <ul> <li>high CCR7</li> </ul> </li> <li>attract desired cells/avoid undesired cells <ul> <li>DESIRED: Th1, CTL, NK <ul> <li>high CCL5, CXCL10</li> </ul> </li> <li>UNDERSIRED: Treg <ul> <li>low CCL22</li> </ul> </li> </ul> </li> <li>resistant to suppression <ul> <li>induce irreversable "final maturation"</li> </ul> </li></ul>
<p>Pros (3) + cons (3) of tolDC tx for RA</p>
<p>Pros</p>
<ul> <li>low toxicity</li> <li>targeted immunosuppression <ul> <li>leaves immunoprotective aspects of system intact</li> </ul> </li> <li>potential to restore underlying defect <ul> <li>i.e. long lasting cure</li> </ul> </li></ul>
<p>Cons</p>
<ul> <li>customised <ul> <li>labour intensive, costly</li> </ul> </li> <li>too focused on a particular Ag <ul> <li>some patients might be multi-antigenic so targeting one may not affect overall disease</li> </ul> </li> <li>risk of enhancing auto-antigen responses <ul> <li>injection of APCs (tolerogenic ex vivo) may become immunogenic in vivo</li> </ul> </li></ul>
<p>AuToDeCRA (description)</p>
<p>Autologous Tolerogenic Dendritic Cells in Rheumatoid Arthritis</p>
<ul> <li>proof of concept study</li> <li>phase I clinical trial (10 pts) <ul> <li>unblinded, placebo-controlled</li> <li>dose-escalation, safety study</li> </ul> </li> <li>DCs loaded with aotologous synovial fluid</li> <li>intra-articular adminstration route <ul> <li>targets diseased tissue <ul> <li>hope for local LN migration</li> </ul> </li> <li>safety <ul> <li>if tolDC worsened RA, it would be localised</li> <li>treatable with steroid rescue</li> </ul> </li> </ul> </li></ul>
<p>AuToDeCRA (major findings)</p>
<p><strong>main conclusion: tolDC therapy is SAFE</strong></p>
<ul> <li>but no effects/benefits on systemic disease actvity <ul> <li>tolDCs do not migrate out of the knee</li> <li>tolDC effects are local, not systemic</li> </ul> </li> <li>tolDCs modulate TCs via IL-10/TGF-B mechanism <ul> <li>2 patients did not have recurrence of knee synovitis</li> </ul> </li></ul>
<p>sipuleucel-T (Provenge)</p>
<ul> <li>cellular cancer therapy</li> <li>DCs + TCs</li> <li>treatment of advanced CaP</li></ul>
<p>DC1 (cDC1)</p>
<ul> <li>CLEC9A / CD141</li> <li>activates Th1 immunity</li> <li>cross-presentation</li> <li></li></ul>
