Cancer Treatment: A New Era Autologous cellular immunotherapy – activated APCs are reinfused into patient to direct immune cells vs tumor cell (ie: sipuleucel-T) Immune checkpoint inhibitors – “release the brakes” on the immune system (ie: ipilimumab, nivolumab, pembrolizumab) CAR-T therapy – chimeric antigen receptor (CAR) T cells Immunovirus – therapeutic cancer vaccine Future directions – BiTE antibodies, DNA methylation signature, TMEM score, magic wands, IDH2 blockers, proteomics, intraoperative radiation, CRISP-R technology Cancer immunotherapy
Patient Case #1: PD-1 Inhibitor ED 33yo male with Hodgkins Lymphoma Apr 2011: standard chemo w/ ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) x6 cycles 2 nd line chemo: GDP (gemcitabine, dexamethasone, cisplatin) 2012: autologous stem cell transplant → recurrence Salvage chemo: brentuximab vedotin (Adcetris®) Salvage chemo: GDP, MOPP (mechlorethamine, vincristine, procarbazine, prednisone), bendamustine Dec 2014: allogeneic stem cell transplant → recurrence Now what???
Immunotherapy: Checkpoint inhibitors Immune system relies on multiple checkpoints to avoid over activation on healthy cells Tumor cells hijack these checkpoints to escape detection CTLA-4 & PD-1 are upregulated on T cell surface in some cancers PD-L1 can be expressed on tumor cells endogenously or induced by association with T cells PD-1:PD-L1 interaction results in T cell suppression (anergy, exhaustion, death) Atkins MB et al. Clinical Care Options slideset 2014.
NIVOLUMAB PEMBROLIZUMAB IPILIMUMAB Drake CG et al. Nat Rev Clin Onc. 2014;11:24-37.
Immunotherapy: Checkpoint inhibitors In melanoma, renal cell, & other tumors, PD-L1 expression is associated with more aggressive disease Inhibiting CTLA-4 & PD-1 can “release the brakes” Checkpoint inhibitors don’t attack the tumor, they set the T cells straight Activity powerful enough to work in the CNS – T cells go everywhere Melanoma patients – on MRI, brain mets are surrounded by tons of T cells Atkins MB et al. Clinical Care Options slideset 2014.
Immunotherapy: Checkpoint blockade Ribas A. N Engl J Med. 2012;366:2517-2519. Priming phase (lymph node) Effector phase (peripheral tissue) T-cell migration Dendritic cell T cell MHC TCR B7 CD28 CTA-4 T cell Cancer cell MHC TCR PD-1 PD-L1 T cell Cancer cell Dendritic cell T cell MH C CD28 B7 CTLA- 4 MH C PD- 1 PD- L1
Immunotherapy: PD-1 inhibitors Nivolumab (Opdivo®) – FDA approval • Melanoma – unresectable or metastatic; single agent or combination with ipilimumab • NSCLC – metastatic; with progression on or after platinum-based chemotherapy and EGFR or ALK therapy if EGFR or ALK positive • Renal Cell – advanced disease who have received 1 or 2 prior therapies Summary – ORR in patients with advanced NSCLC, melanoma, renal cell carcinoma • 65 of 306 patients had ORR (CR or PR) • 30 of those 65 (46%) had response evident at first tumor eval (8wks) • 42 of those 65 (65%) had response lasting >1yr • 35 of those 65 (54%) had response ongoing at time of data analysis • Response persisted off the drug Nivolumab pkg insert , Atkins MB et al. Clinical Care Options slideset 2014.
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