ERIC 2018: Kipps on Research Progress in Treating CLL (chronic lymphocytic leukemia) By Developing Antibodies That Control Key Proteins

By Larry Marion

This is the first of a series of three interviews with Dr. Thomas Kipps that will follow in rapid succession.

Most chronic lymphocytic leukemia patients remain afraid, despite all of the recent development of novel agents such as ibrutinib and venetoclax. While these treatments appear to not only control the disease but may, in some combination, “cure” it, at least in terms of achieving undetectable “minimal residual disease” (MRD), CLL patient worry that they’ll develop resistance to them.

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, review new research on therapies that may help CLL patients, including those that develop resistance to the new novel agents. Drs. Koffman and Kipps met at the European Research Initiative on CLL (ERIC) meeting in Barcelona, Spain in October 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.

Dr. Kipps was instrumental in the development of monoclonal antibodies, which control or destroy CLL related proteins. The most famous monoclonal antibody related to blood cancer is Rituximab, which is commonly used in chemotherapy for CLL, usually in combination with other infusion therapies such as Bendamustine (the combo is known as BR) or fludarabine/cyclophosphamide (FCR). Rituximab also is being tested in combination with the novel anti-CLL agent venetoclax with very promising results.

A new more specific 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. The antibody currently is in an early stage clinical trial as the treatment known as cirmtuzumab.

Key Take Aways:

• A new formulation of rituximab offers subcutaneous injection rather than infusion. It is easy to administer and takes less time than an infusion, according to Dr. Kipps. This new formulation was approved last year by the U.S. Food and Drug Administration.
• While Rituximab has been shown to be extremely effective in controlling CLL in combination with other therapies, it has a major drawback: it attacks good as well as bad B cells.
• The new anti ROR1 antibody, cirmtuzumab, only disrupts the protein on leukemia cells that triggers their growth and spread. Therefore, the antibody does not attack all B cells. “When you target that protein you’re only targeting the cancer cells,” explains Dr. Kipps. “There is less collateral damage to the immune system.”
• The protein ROR1 is also expressed in almost all cancers, especially “primitive” tumors that have the risk of metastasizing or spreading. Two examples: It has already been found in patients with breast, pancreatic and other cancer. It is hard to find on most normal tissue.
• The antibody appears to be well tolerated and could be an appropriate co-treatment with novel agents such as ibrutinib or venetoclax.
• The antibody that targets ROR1 appears to have a long half-life—it remains effective for weeks or a month. Therefore, it may be amenable to monthly or weekly treatment.

Author commentary

As a long-term ibrutinib user, I had worried about becoming resistant to the treatment and what my options would be thereafter. As testing at Ohio State University indicates that I am not at risk of resistance, I am one of the lucky ones. Since a significant percentage of ibrutinib and venetoclax users eventually become resistant, especially when used in the relapsed and refractory setting, research by Dr. Kipps and others that identified ROR1 and its inhibiting antibody offer some assurance that there soon will be new options. Indeed, their research adds to the growing evidence that the future of CLL treatment will relies on drug combination/cocktail or planned sequencing of therapy.

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.

Here’s the Kipps video from ERIC 2018

For more on the research progress of the ROR1 antibody from a year earlier at ASH 2017, read this summary and video:

https://cllsociety.org/2018/07/ash-2017-dr-thomas-kipps-on-the-ror1-antibody-cirmtuzumab/

For more background and basic science on ROR1, how it functions and its importance to controlling CLL, please read this article by one of Dr. Kipps colleagues, Dr. Michael Choi:

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