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Immunotherapy for Colorectal Cancer
Michael Overman, MDMD Anderson Cancer Center
Gastrointestinal Medical Oncology
Immune Infiltrate and Prognosis in Primary CRC: Immunoscore
JCO 2006 Pages et al., NEJM 2005 Pages et al.
411 stage I and II CRC
Deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H)
Tejpar BJC 2009; Koopman BJC 2009
• Mutations in MMR (inherited) or loss of MMR by methylation (acquired) results in microsatellite instability (MSI)
– Increased duplication of tandem dinucleotide repeats (microsatellites)– Resulting increased mutations rate and higher risk of colon cancer– Unique clinicopathological features (lymphocytic infiltrate, Crohn’s-like
reaction, varigated histology, poor differentiation, right sided)
Anti-CD3
MSI-high CRC ≈3% HNPCC
≈12% sporadic
Universal Testing for HNPCC
1158 (31.5)
992(27)
2125 (57.8)
2394(65.2)
3671(100)
No Tested (%)
Moreira et al. JAMA 2012
Revised Bethesda criteria:1. CRC <50y/o2. Synchronous, metachronous CRC or other HNPCC cancer3. CRC with MSI-high histology in <60y/o4. CRC in ≥1 1st-degree relative with hnpcc cancer with 1 cancer diagnosed <50yrs5. CRC in ≥2 1st or 2nd-degree relatives with hnpcc cancer regardless of age
Jerusalem criteria: all CRC <70 years old
dMMR or MSI-H Have Better Outcomes (Prognostic Effect)
0102030405060708090
100
0 1 2 3 4 5Years
% D
isea
se F
ree
HR: 0.51 (0.29-0.89)p=0.009
Untreated (N=515)
MSI-H 80%MSS 56%
5 yr DFS
Sargent, et al. ASCO 2008 and ASCO 2014; Tejpar BJC 2009; Koopman BJC 2009
Stage MSI-H
II 22%
III 12%
IV 3.5%
5-year OS HR 95% OS P-value dMMR pMMR Stage II
Surgery alone (n=307) 90% 78% 0.27 0.10 - 0.74 0.011
Stage III
Surgery alone (n=264) 59% 54% 0.69 0.35 – 1.36 0.283
ACCENT database
14 phase III adjuvant studies
Metastatic MSI-high CRC
Retrospective reivew of 55 metastatic MSI-H pts from MDACC + Royal Melbourne
Hospital, Australia – 14 BRAF V600E (25%)
Goldstein + Overman AoO 2014
BRAF V600E
Schreiber et al. Science 2011
Tumor Antigens:Differentiation (melanocyte differentiation antigens…)Overexpressed (HER-2…)Viral (HPV proteins…)Cancer/testis (MAGE, NY-ESO-1…)Mutational (p53…)
Immunity and Cancer
Matsushita A et al. Nature (2012); 482 (7385); 400-4
Immunogenic methylcholantherene-induced sarcoma cell
lines from Rag2-/- mice demonstrate ≈20% tumor
rate in naïve wildtype mice
Spectirn β-2 R913L mutation predicted and
cloned from TIL
MHC class I
Corbiere et al. Can Res 2012; Robbins J Exp Med 1996; Gaudin et al. J Immun 1999
Peptide In silico HLA nM affinity
A0201SLFEGIDFYT 11SLFEGIDIYT 18
A2403 SYLDSGIHS 5646SYLDSGIHF6
A0201ILDKVLVHP 16730ILDKVLVHL 42
BMS-936550RR: 0/18 CRC
TremelimumabRR: 1/45 CRC
(response duration 15m)
NivolumabRR: 0/19 CRC
NivolumabRR: 1/14 CRC
(response duration >21m, MSI-H pt)
Immune Checkpoint Agents in CRC
Immune Escape Mechanisms in MSI-high CRC
Llosa et al. Cancer Discovery 2014
Invasive FrontStroma
TIL
Ongoing Anti-PD1 or Anti-PDL1 Clinical Trials with MSI-high CRC Subsets
• NCT01876511: Phase 2 study of MK-3475 in patients with microsatellite unstable (MSI) tumors– MSI-high CRC, MSS CRC, MSI-high non-CRC
• NCT02060188: A study of nivolumab and nivolumab plus ipilimumab in recurrent and metastatic colon cancer (CheckMate 142)
– MSI-high CRC, MSS CRC
• NCT02227667: Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal Cancer– MSI-high CRC, TIL high CRC
• NCT02404411: phase I/II study of PDR001 in patients with advanced malignancies– MSI-high CRC, other tumors
• NCT01633970: A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with bevacizumab and/or chemotherapy in patients with advanced or metastatic solid tumors
– MSI-high CRC, other tumors
• A phase 1, open-label study of GSK3174998 administered alone and in combination with anticancer agents including Pembrolizumab in subjects with selected advanced solid tumors
– MSI-high CRC, other tumors
Immune checkpoint in melanoma
Ipilimumab in advanced melanoma
Wolchok et al. Lancet Oncol 2010
Nivolumab/Ipilimumab: Chort 2a (n=16):Nivolumab 3mg/kg + ipilimumab 1mg/kgClinical benefit of 73%G3/4 immmune Aes: 11
Wolchok et al. NEJM 2013
What about combo data in MSI-high CRC?
Nivolumab in frontline melanoma
Robert et al. NEJM 2014
Nivolumab single agentMSI-High CRC
Pre-rectal Xrt Pre-tx Restaging at 4months
Cap/xrt to rectum Nivolumab
Pre-tx Restaging at 4months
Nivolumab
Patient #1
Patient #2
Conclusion
• Test for MSI-high– As universal testing approach for HNPCC– For prognostic relevance in stage II– For clinical trial options in metastatic patients
• Clinical trials of immune-checkpoints in MMR deficient (MSI-high) CRC should be engaged upon
• Targeting PD1/L1 and/or CTLA-4 have demonstrated limited to no activity in MMR proficient CRC
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