ASH 2018: Dr. Kipps Updates on ROR1 Progress

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By Larry Marion

This is the second part of the ASH 2018 interview with Dr. Kipps on targeted antibodies aimed at the chronic lymphocytic leukemia cells and the third of a 3 part series starting with an interview at ERIC  2018. For links to the ERIC interview, click here. For the first part of this interview, click here.

In this video,  Dr. Brian Koffman, a CLL patient, family doctor and chief medical officer and EVP of the CLL Society and Thomas j. Kipps, M.D. of the Moores Cancer Center at the University of California at San Diego, discuss the latest insights from Dr. Kipps’ pioneering work developing an antibody to defeat leukemic cells.  Dr. Kipps’ enthusiasm is palpable. Drs. Koffman and Kipps met at the American Society of Hematology (ASH) annual  meeting in San Diego in December 2018.

Dr. Kipps is a world-renowned cancer researcher. He is a Professor of Medicine and holds the Evelyn and Edwin Tasch Chair in Cancer Research, and Deputy Director of Research Operations at Moores. He also is the Director of the Blood Cancer Research Fund at Moores. The Blood Cancer Research Fund concentrates on developing cures for all types of blood related cancers, specifically CLL.

The new antibody Dr. Kipps co-developed inhibits a protein known as receptor tyrosine kinase like orphan receptor 1 (ROR1). In preclinical testing the antibody has been shown to be extremely effective in disrupting that protein on top of CLL and other cancer cells. Furthermore, the antibody may be particularly effective in reducing or eliminating resistance to ibrutinib or venetoclax.

“We think we may have an answer to patients who are resistant to the new therapies,” Dr. Kipps says. “We’ll be able to make a special delivery to your leukemia cell that’s specific and ptoentially able to eradicate the cells.”

The antibody currently is in an early stage clinical trial as the treatment known as cirmtuzumab. For more information about ROR1 and how it works, click here:

https://cllsociety.org/2017/09/cirmtuzumab-whats-ror-ing/

Key take aways

• In Phase I clinical trials the antibody dose levels were increased to very high levels but were well tolerated by patients. No infusion reactions, no chills, very minor toxicity, Dr. Kipps noted. And it wasn’t clear if the minor toxicity was due to the drug.
• The antibody has an extremely long half life. While some antibodies have a half life of a few hours or days (half of their potentcy dissipates in a short time), the anti ROR1 antibody has a half life of 30-32 days, so it could be dosed once a month.
• While the initial clinical trial phase was just to determine safety and dose level toxicity, it became clear that the antibody was clearing leukemia cells from bone marrow. White blood cell counts and lymph node size were both reduced. While no patient achieved even a partial response using standard criteria, it was clear that the antibody was affecting ROR1 and therefore the leukemia cells ability to grow and spread.
• A study is underway testing the efficacy of the antibody on breast cancer cells, due to certain similar characteristics with the leukemia cells. “What we learn about CLL may actually apply to other cancers.”
• Patients using ibrutinib have ROR1 working in “overdrive,” so the idea of combining ibrutinib and the ROR1 antibody is very attractive, at least in animal simulations done to date. “There seems to be an additive effect when blocking two surivival pathways to the escape hatch the tumor cells try to use to evade from dying,” explains Dr. Kipps.
• Leukemia cells with high levels of ROR1 also typically have high levels of BCL-2 (the protein attacked by venetoclax). And those patients typically are getting less relief from venetoclax. “Combining the ROR1 antibody with venetoclax could be very exciting,” Dr. Kipps says.
• Another benefit of the ROR1 antibody may be its ability to deliver other information to tumor cells. “All you have to do is attach whatever you want to the ROR1 antibody and put it on a linker that can be dissolved when it gets into the” cell. An investigations new drug application (NDA) clinical trial is underway to test the use of this antibody with another drug.

Author commentary

While the biology is complex for the layperson and even a 14-year CLL veteran like myself, it is worth listening to Dr. Kipps’ insights. CLL patients should understand that even the new novel agents currently available may need to be supplemented at some point, depending on patient needs. The era of personalized treatment will become ever more precise in the next few years.

Thanks for reading

Larry Marion

Larry Marion is a CLL survivor who has been using ibrutinib for more than five years. He begins venetoclax treatment in May, in the hope that he may be able to terminate anti-CLL drug treatment one of these days. Marion is a former science writer and editor for various business and technology publications.