ASH 2017: Dr. Thomas Kipps on the ROR1 Antibody, Cirmtuzumab

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.

Take Aways:

• 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:
  A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies
• 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.

Stay strong.

We are all in this together

Brian

ASH 2017: Dr. Adrian Wiestner on Resistance Mechanism in CLL (chronic lymphocytic leukemia)

I had the opportunity to interview Dr. Adrian Wiestner from the National Institutes of Health at ASH 2017 in Atlanta GA about his and other researchers work on how CLL cells become resistant to ibrutinib and venetoclax.

Take Away Points:

• Ibrutinib works so well in chronic lymphocytic leukemia because it blocks the B-cell receptors (BCR) by binding to Bruton’s Tyrosine Kinase (BTK). This blocking of the BCR leads to cell death.
• About 7-8 out of 10 patients who become resistant to ibrutinib develop a mutation C481 that prevents it from it binding and thus fully blocking BCR, allowing the CLL to progress.
• PCLƔ2 mutation is another cause of resistance as it turns back on the BCR pathway and gives a lifeline back to the chronic lymphocytic leukemia cells.
• Cells with the PCLƔ2 mutation tends to grow more slowly and the CLL tends to clinically progress more slowly.
• Notch1 mutation can be associated with early progression on ibrutinib which is often not CLL but instead Richter’s Transformation that carries a poor prognosis.
• Many patients do well on ibrutinib who have a Notch1 mutation.
• Richter’s is rare after the first year on ibrutinib suggesting that blocking B-cell signaling may block the stimulation that leads to Richter’s
• Less is known about the mechanism of venetoclax resistance, but upregulation of MCL-1 might play a role.

Conclusion:

While the numbers are small, we are starting to better understand the mechanisms of resistance for some but not nearly all patients who progress on ibrutinib. Our understanding of venetoclax resistance is much less mature. As this research develops, there is reason to be optimistic that we can develop drugs to overcome the resistance.

Here is my interview with Dr. Wiestner from ASH 2017 in snowy Atlanta Georgia:

Here are links to some of the research referenced by Dr. Wiestner

• Mechanisms of Venetoclax Resistance in Chronic Lymphocytic Leukemia
• Dissecting the Role of Individual Bcl-2 Members in Response and Resistance to Ibrutinib or Venetoclax in CLL
• Apoptosis Resistance and NOTCH1 Mutations Impair Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) Patients Treated with Ibrutinib

Here is more on resistance from Dr. Furman from our website.

Thanks for reading.

Stay strong

We are all in this together.

Brian Koffman

He Did It

Hi,

Stan Kurtz and his team, with help from so many of you, Did it. He swam the Catalina channel and raised his goal of over $25.000 for the CLL Society! Thanks to all who gave, but it's not too late to share in there joy. Consider a tax deductible (in the USA) got of $22, one dollar for each mile he swam in over 12 hours in the Pacific Ocean. Or more. It was an exhilarating and exhausting for Patty and me just being on the boat.

Now I need to get some sleep. 

Thanks 

SEE: https://www.gofundme.com/swimcatalinaforleukemia. The swim was on the local TV news. This will help us to do so much more for others dealing with CLL.

Lot's of pictures and videos on our and his FB page,

Stay strong.

We are all in this together.

Brian

http://cllsociety.org