At ASH 2017 held in December in Atlanta, Dr. Thomas Kipps from the Moore Cancer Center at UCSD in San Diego, CA talked about an exciting new target for very specifically killing off chronic lymphocytic leukemia cells while sparing normal cells, including normal B lymphocytes.
Dr. Kipps is one of the leading CLL researcher and has pioneered the work on a new antibody, cirmtuzumab that targets ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1).
Because ROR1 is found nearly exclusively on cancer cells, an antibody against it may be the holy grail of antibodies, one that hits only the cancer cells with few off target effects.
- ROR1 is an embryonic protein that may help the embryo develop new distant organs.
- By birth it has largely disappeared from normal cells, but it can be found on the surface of many cancer cells including CLL cells.
- ROR1 is involved in keeping CLL cells alive even when their B-cell receptor (BCR) is blocked by drugs such as ibrutinib.
- Cirmtuzumab is an antibody against ROR1 that it very specific in hitting just that target.
- Early studies used extremely low doses and it was only given four times.
- Cirmtuzumab has proven to be safe in this phase 1 trial with no serious side effects including no significant infusion reactions.
- The ROR1 antibody has a long half-life of 21 days.
- While the early trial was for safety, there was clear evidence of efficacy in the few relapsed and refractory patients who received the higher doses of 1 mg per kilogram with a median progression free survival (PFS) of 259 days using that suboptimal dose.
- The combination with ibrutinib appears to be result in higher kills rates of the chronic lymphocytic leukemia cells by blocking two separate signaling pathways necessary to keep the cells alive.
- There are ongoing clinical trials looking at the combination of cirmtuzumab and ibrutinib. Here is a link:
- While adding antibodies has historically not improved ibrutinib efficacy, cirmtuzumab is different in that it not just targeting a surface protein but is blocking a pro-survival pathway critical for CLL.
- Cirmtuzumab also may be important in killing of cancer stem cells, which if proven, should reduce the risk of late relapses.
We have many exciting treatments for chronic lymphocytic leukemia, but cure is still elusive. It is still very early in the story, but he can sense Dr. Kipps’ excitement and his hope that cirmtuzumab, when used in smart combinations might be part of the mix that leads to what we all dream of, namely being able to say: I used to have CLL.
Here is my interview with my doctor, Dr. Thomas Kipps from UCSD. It’s 17 minutes, but Dr. Kipps is a great teacher.
Here is a link to the referenced ASH abstract: Durable and Specific Inhibition of ROR1 Signaling Associates with Prolonged Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Treated with Cirmtuzumab
For more of ROR1 and cancer stem cells, see this prior interview from ASH 2014 with Dr. Kipps.
Thanks for reading.
We are all in this together