1. Liver transplantation for colorectal cancer liver metastases
08/07/17
Liver transplantation for colorectal cancer liver metastases
Vivian McAlister
BonMOTS
Wednesday 24 Jan 2018

2. Liver transplantation for colorectal cancer liver metastases
08/07/17
Liver transplantation for colorectal cancer liver metastases
No conflicts of interest

3. Liver transplant for CRC mets:
08/07/17
Minimum survival expectations and access to liver transplantation
Results of liver transplantation for CRC mets
Interaction of chemotherapy and immunosuppression
Proposed inclusion criteria
What is the ideal immunosuppressive / cancer suppressive drug regime?

4. 08/07/17

5. ALPPS Results in 47 of 58 patients Median DFS – 12 months
08/07/17
ALPPS
Results in 47 of 58 patients
Median DFS – 12 months
3 year disease free survival – 18%
3 year overall survival - 50%

6. 08/07/17

7. Minimum survival expectation for listing is 50% at 5 years
08/07/17
Minimum survival expectation for listing is 50% at 5 years

8. 08/07/17

9. 08/07/17
FIGURE 1. Overall survival after liver transplantation for metastases from nonresectable CRC. The KM plot shows overall survival from the time of liver transplantation (red line). Stapled lines shows 95% CI for the KM plot. Blue line shows DFS. All deaths were due to the underlying cancer disease. No patients were lost to follow-up.

10. 08/07/17

11. 08/07/17

12. 08/07/17
Kaplan-Meier OS curve from time of progressive disease for patients included in the liver transplantation group (SECA study, hatched line, n = 20) and the chemotherapy group (NORDIC VII study, solid line, n = 45)

13. 08/07/17

14. 08/07/17

15. 08/07/17

16. 08/07/17

17. 08/07/17

18. 08/07/17

19. 08/07/17

20. General Surgery Experimental laboratory (GSEL)
08/07/17
General Surgery Experimental laboratory (GSEL)
Collaboration of surgeons and basic scientists
8th Floor University Hospital
Collection and processing of tissue from surgical procedures in UH
To define the basis for innovative care that improves the outcomes for patients undergoing surgery

21. HepatoBiliary Surg Nutr 2016;5(3):204-208
08/07/17
HepatoBiliary Surg Nutr 2016;5(3):

22. 08/07/17

23. Radial migration of human HCC in 3-D culture with 5FU, TAC or SRL
08/07/17
Radial migration of human HCC in 3-D culture with 5FU, TAC or SRL

24. 08/07/17
Concentration of 5FU combined with TAC or SIR in mouse plasma and liver.

25. Uptake of 5-FU by cell-lines in culture with TAC or SRL
08/07/17
Uptake of 5-FU by cell-lines in culture with TAC or SRL

26. 08/07/17

27. 08/07/17

28. 08/07/17
Department of General Surgery
Effect of chemotherapy on pancreatic cancer cell line, PANC1, 2D culture * * * * * *
* p < 0.001 * *
Both looking at traditional chemo regimens…. 28

29. Effect of immunosuppression on chemotherapy in PANC1 2D culture
08/07/17
Department of General Surgery
Effect of immunosuppression on chemotherapy in PANC1 2D culture * * * * * *
* p < 0.001 * *
As well as our novel regimens 29

30. Comparing 2D and 3D culture PANC1
08/07/17
Department of General Surgery
Comparing 2D and 3D culture PANC1
p < 0.01
p < 0.01
p = 0.58
p = 0.69
* p < 0.01 * *
p = 0.13
p = 0.19
p < 0.01
p < 0.001
Finally, comparing 2D and 3D TC
looking at individual treatments, we can see that chemotherapy has an effect on tissue culture in both 2d and 3d that is similar but not identical.
Spheroids using are very small
Validated up to a certain size, we’ve stay within the size. Therefore may be seeing more permeation than we would otherwise.
As we can adjust technique and employ larger spheroids, we can qualify acid phosphatase assay for that size and potentially see different outcomes * * 30

31. 08/07/17
Liver transplantation for colorectal cancer metastases requires clinical expertise managing cancer chemotherapy and immunosuppression simultaneously

32. Passardi et al. Int J Mol Sci. 2017 Jun; 18(6): 1324.
08/07/17
Passardi et al. Int J Mol Sci Jun; 18(6): 1324.

33. 08/07/17

34. Haeryfar Lab, Western University
08/07/17
Haeryfar Lab, Western University
Memarnejadian A et al. PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8(+) T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination.
J Immunol. 2017;199:
Shaler CR et al. Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.
Cancer Immunol Immunother. 2017;66:
Shaler CR et al. MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression.
PLoS Biol. 2017;15:e

35. 08/07/17

36. Lee and Lee. Gastroenterol Res Pract. 2017; 2017: 7521987.
08/07/17 .
CEA mediated events that create a micro-environment for successful metastatic seeding.
Lee and Lee. Gastroenterol Res Pract. 2017; 2017:

37. 08/07/17

38. 08/07/17

39. No extra-hepatic disease
08/07/17
Indications for liver transplantation in patients with metastatic colorectal cancer
Unresectable
Stable
No extra-hepatic disease

40. Minimize T-cell inhibition Adjuvant chemotherapy
08/07/17
Post-transplantation considerations in liver recipients transplanted for metastatic CRC
Minimize T-cell inhibition
Adjuvant chemotherapy
Exploit positive interactions between chemotherapy and immunosuppressive therapy

41. Liver transplantation for metastatic CRC: research opportunities
08/07/17
Liver transplantation for metastatic CRC: research opportunities
Differentiating the anti-cancer and the anti- donor immune responses
Create an intra-graft environment that is inhospitable to cancer
Develop grafts that have anti-CRC properties

42. 08/07/17
Thank you

43. 08/07/17

44. 08/07/17