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ASH 2019: Dr. Adrian Wiestner on Bispecific Antibodies for Treating CLL (Chronic Lymphocytic Leukemia)

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At the American Society of Hematology Annual meeting held live in Orlando, Florida on Dec. 2019, the cutting edge of CLL and all blood cancer research was presented. It is the most important blood cancer meeting of the year and the most important sessions at ASH are the plenary sessions and the late-breaking abstracts. 

For years we have been spoiled as many of the biggest advances reported have directly helped CLL patients.   

At this ASH meeting, one of the prestigious plenary papers was about an advancement in related blood cancers, but not yet studied in CLL, namely new data on a bispecific antibody. 

In way of perspective, CLL management has been revolutionized by two innovations over the last decade 

The best known of these therapeutic revolutions has been the introduction of targeted therapies lead by the approval of ibrutinib in 2014.  This was followed by a growing victory parade of “small molecules” that can be taken orally to control the cancer. 

Targeted therapies usually work by blocking a pathway the CLL has hijacked and subverted to its own nefarious purpose, thereby selectively killing off the cancer cells addicted to that pathway while sparing the normal blood cells. 

The other equally significant revolution has been the harnessing of the immune system, led by rituximab, a monoclonal antibody (MAB) that was original approved in 1997 for Non- Hodgkin Lymphoma or NHL (CLL is a subtype of NHL) and in 2010 for CLL specifically. MABs, such as rituximab and obinutuzumab (Gazyva), attach to a surface protein or marker found on CLL cells, in their case CD20, that is also found on normal B cells marking them for destruction by the T cells. 

Antibodies are Y-shaped and we now have the technology to have two different targets on one antibody, a bispecific antibody. One attaches to the CLL cells and the other collars the T cells through targeting CD3 on T cells and pulls it into proximity to ensure the killing happens. 

I wrote up this fun short explanation of bispecific antibodies that you can read here that also reviews MABs and the most basic material on immune therapies. I highly recommend you take a look at it if this article is a challenge. It will provide you with some helpful background. 

I caught up with Dr. Adrian Wiestner from the NIH at ASH 2019 to discuss bispecific antibodies as they relate to chronic lymphocytic leukemia. 

Takeaways 

  • Immunotherapy is a more focused and powerful way to defeat cancer. 
  • Bispecific antibodies are emerging as the next evolution in blood cancer management. 
  • There are good preclinical results that suggest they will work well in CLL. 
  • They are similar to CAR-T, which is also an immune therapy involving T cells, but bispecifics have the advantage of not needing bespoke manufacturing for each patient. Therefore, they should be more readily available as they likely would be “off the shelf” as is rituximab. 
  • There is reason to believe that when used in combination with a BTK inhibitor such as ibrutinib, they would work even better as ibrutinib improves T cell function. 
  • Combinations of immune therapies and targeted therapies such as ibrutinib and obinutuzumab have already proven successful in CLL. 

Conclusions: 

The best future treatment to knock out CLL will likely include a mix of approaches and one of those approaches will probably be an immunotherapy such as bispecific antibodies. 

Here is my ASH interview with Dr. Adrian Wiestner . 

Also listen to Dr. John Pagel, one of our directors, interviewing Dr. Schuster from U. Penn. on his groundbreaking research on the bispecific antibody, mosunetuzumab, in aggressive NHL at ASH 2019 as referenced by Dr. Wiestner. 

Here is that plenary abstract:Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines. 

Mosunetuzumab and other bispecific antibodies are not yet in clinical research in CLL, but they should be. We need multiple effective, safe, and focused ways to defeat our CLL. We need to let researchers and industry know that while we are enormously grateful for all the advances in CLL, we still have unmet needs, including curative therapies. 

Thanks for reading. 

Stay strong. Stay safe. We are all in this together. 

Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.