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Saturday, March 24, 2012

A Cancer Cells Walk, A Research Opportunity

Randomness rules our lives. It also rules cancer. This paper is a glimpse into that randomness. It looks at cells after they have gone to the dark side to became part of what we call cancer. Scientists found that a single tumor can contain a number of genetic differences. A single biopsy only paints one tiny part of a cancer's molecular picture.

Once again we have a scenario akin to the testing of the Cargo Cult Science speech rat maze. We begin with our test subject, a single target drug. We put it into our maze, the human body. We assign significance to certain outcomes such as the patient getting better, and we set a time limit for collecting data.  The question remains, how much do we know about our maze?

Seattle Genetics had their first product approved by the FDA last year. ADCETRIS is indicated for the treatment of:

  • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)
  • HL in patients who are not ASCT candidates after failure of at least 2 multi-agent chemotherapy regimens
  • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen

The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS. There is certainly no data on the cells found throughout the tumors.

Seattle Genetics took advantage of a pattern.  CD30 is expressed in both HL and sALCL but has limited expression in healthy tissue. Bio-technicians then made an antibody against CD30 - ADCETRIS (brentuximab vedotin). The antibody binds to CD30 on the cell surface which somehow initiates internalization of the ADC-CD30 complex. Inside the cell, MMAE is released via proteolytic cleavage. Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death.

That is a highly detailed description of how the drug works.
"CD30 is expressed in both HL and sALCL but has limited expression in healthy tissue."
Is this true? Tumor samples have been shown to have different cell populations across their diameter. In this study diploid cells were found throughout the tumor. However, some of the cells tested were not diploid. These were found at only one end of the sample, fading out gradually towards the middle. Two other varieties (near-tetraploid) were found at the other end. Almost all of the diploids were normal cells, and most of those were immunocytes that had infiltrated the tumor.

What is the composition of the cancers being treated by ADCETRIS? In a 2010 clinical trial produced their official data set: 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission. Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumors shrinkage. What exactly can we take away from such descriptions of cancer and how we treat it? What do we know about the Seattle Genetics mechanism of action proposal and the end results?

In the case of Seattle Genetics, we have seen cargo. A plane landed. We don't really know much about the plane or how it got here. Retraction Watch reported on such a case just this week. In this case, a method of measuring antibody-antigen binding led to faulty data which, not surprisingly, supported the outcome that was hoped for. There was a plane on our runway but upon closer inspection it was not real. 

The information we now have on tumor cells and the widespread "mutations" makes us wonder about single target treatments for cancer. Our industry tells us they work, sometimes very well. We here at the CCS see that claim as a research project. Why do they work? The possible fact that they work, coupled with the possible fact that tumors are not a homogeneous group of cells, demands an explanation. All a leader has to do is set a group of scientists into the laboratory to try and reconcile this contradiction. Then set another group of people into the lab half way across the world to do the same thing. Then another group! It is an important question. Drug companies aren't simply making pills that make money. They impact our understanding of the human body and the diseases we get. They create knowledge. Is it true?


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