Immunotherapy drugs could treat cancer patients in silico expert reports

Modern every-day immunotherapy (also called checkpoint inhibitors) can be repurposed to treat cancer patients. These drugs work on a patients immune system to eliminate harmful cells. Commercially available cancer patients often end up on checkpoint inhibitors because of a genetic defect in their cancer but another gene mutation may have fallen out of favor. The gene mutation that generates the defect has been all but silenced in 99 percent of patients but the gene mutation that constitutes the defect was clearly not present 17 years ago. It is now abundantly clear that the same mutation occurred in 70-80 percent of the earlier groups that developed advanced cancers says Martin Dale Peterson Ph. D. director of the C. S. Mott Childrens Hospital Medical Centers Tumor Institute and Professor in the Department of Neuroscience at University of California San Francisco.

Pederson and his collaborators reported their findings today in the Annals of Oncology. Co-senior authors are Steven W. Ganz MD and James D. Sheahan MD professors of Pathology and Pathology-Immunology at UC San Francisco.

In 1990 two of the researchers were the first to report that the cancer gene TRIM32 was mutated in patients with very-low grade non-small cell lung cancer (NSCLC) the most common type of NSCLC. That gene mutations are present in 70-80 percent of NSCLC tumors. In 2000 another pair of researchers Mahesh Patal Ph. D. and Brendan F. Sullivan Ph. D. reported the first report of TRIM32 mutations in a mouse model of CSCLC. Using a mouse model of triple-negative NSCLC Peterson and colleagues showed that these mutations previously hidden in plain sight were present in 80-90 percent of that models tumors. Then over this period of time we discovered that in skin melanoma (NSCLC) TRIM32 mutations never occurred in any of the tumors compared to 60-90 percent of those with normal TRIM32 mutations and 56 percent of patients with advanced NSCLC or HER2-negative NSCLC the researchers wrote in a series of articles published in Blood and Cancer.

Since then numerous markers associated with NSCLC have been identified that can be used to predict which patients are at risk of developing other types of cancers. For example markers for selective TRIM32 destruction were found in almost all of those who developed NSCLC. The fact that even with current effective therapies the mutations that cannot be prevented are most often found in the earliest time points when patients are possibly most vulnerable to success of immunotherapy represents truly miraculous performance in our effort to treat such a prevalent and treatable disease Peterson says.

In the current paper the researchers described two preventive drugs that patients with patients with NSCLC can take as a combination: a protein inhibitor called Revlimid therapy and a drug-based therapy called nivolumab. These combination agents represent antixir-like compounds that can be repurposed to eliminate T-cell-targeted therapies for the treatment of NSCLC as well as other cancers that we hope will benefit from combination immunotherapy the researchers wrote.

Valvel Pressman MD and his colleagues at Germanys Centrum Jena and University Hospital Cologne have already used the combination agents in their most common cancer model of glioblastoma (brain) cancer. In our work with this group we conducted a case series that is dramatic in its completeness and reproducibility namely having included blinded patients both active and non-active. Their tumor lines were analyzed at 21 24 28 and 32 weeks and not only at 21 24 and 28 weeks the authors wrote. To determine the potential relapses but also the frequency of relapses three additional measures were taken. The first measure a patient turnover reflected the number of relapses at 21 and 24 weeks. It declined from 32 weeks to 15 weeks at both 24 weeks. The second a patient relapse was taken at 30 and 32 weeks and at 32 and 36 weeks respectively sake of comparison both markers did not decline even with the termination of treatment. With each updated mark the treatment had less chance of being discontinued. In the third and as the two markers in the progression chain were placed in agreement the decision to discontinue treatment was made. In the end the therapy just failed in just two patients.

Drug repositioning is a common procedure for doctors who want to see if immunotherapies can cure the disease. Many of these specialty groups are looking to temper the immune system and reprogram it. This is especially effective because some drugs in the repositioning formulas have been approved by the U. S