Today’s Innovations are Tomorrow’s Cancer Treatments
Published April 15, 2019
According to the American Cancer Society, one in every six deaths worldwide can be attributed to cancer, more than HIV/AIDS, tuberculosis, and malaria combined. While steady research progress has saved the lives of countless cancer patients — much work remains. Recently, we sat down with two cancer researchers who are challenging traditional research paradigms to better inform new therapies.
Reversing the Translational Model
Translational medicine or “bench to bedside” is the near universal method for developing cancer treatments, but Padmanee Sharma, MD, PhD, a professor at The University of Texas MD Anderson Cancer Center is reversing this time-tested approach.
Instead of bringing newly devised treatments from the lab to patients enrolled in clinical trials, she is first bringing patients’ clinical data into the lab for researchers to study. “We’re collecting samples from patients in clinical trials, especially immunotherapy trials, and trying to understand how their immune system is evolving," explained Dr. Sharma. "The immune response is a very dynamic process, which means that the anti-tumor immune response has been evolving and differentiating in some cases for years before a patient presents with a finding of cancer."
"Although we have great mouse models, these models are not able to mimic the longitudinal and dynamic human immune response that develops over years,” she said. “The patient remains the best model.” With the patient’s clinical info, researchers try to understand the patient’s immune system and generate hypotheses that they think will help improve the patient’s treatment regimen.
“Immunotherapy is a match for cancer because this treatment targets the immune system, not the cancer cells...”
Dr. Sharma’s research is focused on immunotherapy approaches which, “unleash the power of the immune system to reject cancer,” she explained. “Immunotherapy is my idea of precision medicine. Most people think of precision medicine as therapies against specific ’driver’ genetic mutations, which are mutations in the cancer cells that enable development and survival of cancer cells, but since cancer cells are constantly evolving and developing new mutations, it may be difficult to develop targeted treatments against each new mutation."
"Immunotherapy is a match for cancer because it targets the immune system, not the cancer cells, and the immune response is constantly evolving in each patient’s body generating precise and specific T-cell responses against the mutations, regardless of whether the mutation is a ’driver’ or ’passenger’ mutation."
“Immunotherapy can also be combined with other treatments such as surgery, radiation, chemotherapy, and targeted therapy because we can take advantage of the fact that these therapies are helping to kill some cancer cells, with subsequent recognition by the immune system, which can be enhanced with immunotherapy agents to drive additional anti-tumor responses as well as elicit development of memory immune responses to enable protection against cancer recurrence,” finished Dr. Sharma.
Tracking the Evolution of Tumors
Part of the need for Dr. Sharma’s approach stems from the complex cellular makeup of cancer, referred to as tumor heterogeneity. Within every patient’s tumor is an opportunity for Darwinian evolution, where specific cancer cell populations (subclones) are selected based on advantageous characteristics like metastatic ability, drug resistance, or immune escape.
“We're trying to understand how a lethal metastatic subclone evolves ... And ultimately use all of that information to develop better diagnostic approaches, better clinical trial designs, and hopefully better therapies..."
“This becomes a problem as the cell to cell variation, and clone to clone variation leads to variation in tumors, and is the ultimate challenge in developing effective cancer treatments,” said Charles Swanton, FRCP, FRS, PhD from The Francis Crick Institute. This is why there are few successful one-size-fits-all approaches to therapy in oncology.
Together with a team of leading researchers, Dr. Swanton spearheaded the TRACERx (TRAcking Cancer Evolution through therapy (Rx)) lung study, which hopes to transform our understanding of non-small cell lung cancer in particular and cancer in general by identifying the relationship between intratumoural heterogeneity in lung cancer tumors and poor clinical outcomes.
“Intratumoural heterogeneity is the difference in tumor subclones within the same patient, either within the primary site, between the primary metastatic sites, or between metastasis,” explained Dr. Swanton. “We're trying to understand how a lethal metastatic subclone evolves from a heterogeneous primary tumor, and whether we can detect and monitor evolution in real time in patients' blood to track evolution during the disease ... And ultimately use all of that information to develop better diagnostic approaches, better clinical trial designs, and hopefully better therapies; ultimately, to control the disease for longer."
Combining Lessons from Different Fields
With their powers combined, the approaches taken by Drs. Sharma and Swanton are critical for building a complete picture of the inner workings of cancer. Knowledge of the evolution and origins of different tumor clones will provide new targets to prime the host immune system, allowing it to destroy cancer cells and reduce the chances of disease recurrence.
In fact, work in this direction is already underway as Dr. Swanton is involved in setting up a company that will develop immune-based therapies targeting the mutations identified in the trunk of the tumour’s evolutionary tree- so-called- clonal mutations. Thus, as Dr. Sharma states “The new realm of cancer immunotherapies should be seen as one of hope for all patients.”
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