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Rene and Edward Chee
Immunotherapy in Canada?

Questions asked by a reader regarding a colon cancer patient:

Past treatments:
- primary tumor surgically removed, followed by chemotherapy (fluorouracil, oxaliplatin, leucovorin), that led to side effect of persistent numbness in hands and feet
- 1 metastatic lung tumor surgically removed (1cm)

Current tumor situation:
- 3 metastatic lung nodules (3-5mm each)
- 1 possible metastatic liver lesion
- MMR (mismatch repair) normal

Current treatment:
- chemotherapy (Capecitabine) - not curative, as it will only reduce the recurrence of colon cancer by 5-10%

1) What immunotherapies are available in Canada, specifically in Vancouver, British Columbia?

2) Any thoughts on an immunotherapy strategy with respect to an article from Science Daily, June 29, 2016, titled "Anti-PD-L1 immunotherapy responsive in microsatellite-stable mCRC comb with MEK inhibition."

Answer:

There are 2 main points I would like to highlight from the article "Anti-PD-L1 immunotherapy responsive in microsatellite-stable mCRC comb with MEK inhibition." you referenced:

1) “Microsatellite instability-high colorectal cancers are associated with a greater number of mutations and are therefore more responsive to immunotherapy with PD-L1/PD-1 blockade.”

If the patient shows high mutations, they will most likely be more responsive to immunotherapy as the tumor looks more “foreign” than normal cells. Thus, if the tumor has problems with the mismatch repair genes, thus generating more mutations, the tumor will elicit a stronger immune response. However, this patient has normal mismatch repair (MMR) genes.

But, the fact that the tumors are still growing after having gone through a chemotherapy regimen may imply that the current tumors are accumulating more mutations. Thus, this patient’s tumors may have enough mutations to elicit an immune response.

2) “Preclinical studies have suggested that a MEK inhibitor can make a tumor more responsive to immunotherapy by increasing the number of active immune cells -- such as CD8+ cells -- in the tumor, and increasing the expression of factors that cause the immune system to be more active.”

DHA, which is a component of fish oil (discussed in Chapter 15 as a form of dietary immunotherapy), and can be gotten from algae oil, may act as a MEK inhibitor, as discussed in this paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179420/) So perhaps the omega 3-6 diet discussed in Chapter 15 may be an easier way to obtain the same effect as MEK inhibitors.

Also, the patient has 4 tumors: 3 lung nodules and 1 in the liver. These tumors can be killed with cryoablation (Chapter 11 and Chapter 14). This not only kills the tumor, but leverages the dead tumor as a cancer vaccine, to train the immune system to recognize the cancer as “the bad guy”, which is a very important component of immunotherapy. Even if the tumor doesn’t have enough mutations (as discussed above), the high inflammation caused by the cryoablation at the site of the tumor will trigger the immune system to recognize the tumor as “foreign”.

The success of cryoablation and whether a difficult tumor can be cryoablated depends on the experience of the doctor performing the procedure. The most experienced cryoablation doctor in the US is Dr. Peter Littrup (Brown University, Providence, Rhode Island), who has treated patients from Vancouver, BC. There is also a doctor who does cryoablation in Vancouver, BC. He is not as experienced as Dr. Littrup, but may be able to treat tumors that are easier to treat and not in critical locations: Dr. David Liu, Vancouver General Hospital (http://doctor-finder.sirweb.org/details.cfm?xid=1067401) I would contact both doctors to see whether all 4 tumors can be cryoablated.

After soldier T cells are generated to attack the tumor (from cryoablations and DHA), immunotherapies such as PD-1 (discussed in Chapter 7) can complement the immune attack by removing the tumor defenses. PD-1 (Opdivo or Keytruda) is approved in Canada for other cancers (melanoma, lung cancer, bladder cancer, etc). You will need to ask doctors or medical professional in Canada whether doctors can prescribe PD-1 off-label, since it’s already been approved for several other cancers, just not colon cancer yet. If it is possible, you will need to look for a doctor who is willing to prescribe it.

Another way to obtain PD-1 would be to look for US clinical trials. I’ve heard it’s hard to get into PD-1 trials even for US patients, due to the large demand. But it’s worth a try to call the clinical trial contacts to see if the patient can qualify. Info to find US clinical trials are in Chapter 16 - especially look up the Cancer Research Institute Clinical Trial Finder.