MD Anderson and the three pillars of modern cancer treatment

Chemotherapy

Emil J Freireich, M.D., clinical professor of Leukemia

When Emil Freireich, M.D., arrived at the National Cancer Institute (NCI) in 1955 to head its leukemia program, the disease was a virtual death sentence. Newly diagnosed patients soon died, usually from massive hemorrhaging or infections.

“Back then, the treatment for acute leukemia was very primitive,” says Freireich. “Chemotherapy drugs had recently become available, but patients died before the drugs had a chance to work.”

To buy time for patients while the drugs killed cancer cells, Freireich knew he needed to halt the nonstop bleeding that is the hallmark of leukemia.

He conducted studies that revealed patients’ bleeding was caused by an insufficient number of platelets — the tiny, colorless discs that circulate in blood and promote clotting. Further studies by Freireich showed that platelets needed to be obtained from freshly donated blood.

“Platelets in blood only last 48 hours,” he explains. “At the time, blood bank protocol specified that the oldest blood on
the shelf be used first. So the platelets patients were getting didn’t work — they had already expired.”

These findings inspired Freireich to help invent a machine to separate blood into three components: plasma, red blood cells and white blood cells. Separating the blood into parts let patients get only the specific part of the blood they needed to combat infections, control hemorrhaging and help manage other complications of cancer and its treatment. Later models are used around the world today.

With bleeding as a cause of death essentially eliminated, Freireich, who was assigned to the pediatric leukemia ward, turned his attention to curing children.

Another difficult-to-treat disease, tuberculosis, recently had been cured by administering three drugs simultaneously. When given separately, they didn’t work.

Freireich believed this approach might work for leukemia as well. So he began combining chemotherapy drugs instead of giving them one at a time.

First he administered two of the highly toxic drugs, then three. With each addition, children became sicker from the drugs’ side effects. Some almost died. When he upped the ante to four drugs in a 1961 trial, an outcry arose from the medical establishment. Freireich’s toxic cocktail would kill the children, they said. Instead, 90% went into remission immediately.

Once children were in remission, Freireich continued their four-drug regimen for a full year to kill any residual cancer cells. That exact strategy, called early intensification, is still used today, and the cure rate for childhood leukemia is 92%.

“The disease recurs in some patients, but not many,” Freireich says. “Most are cured for the duration of their lifetime. Their survival rates are the same as for people who hadn’t had leukemia.”

He next applied this approach to Hodgkin’s disease, also rendering it curable in many cases.

Combination chemotherapy is now a standard treatment for a wide range of cancers, including breast, bone and testicular, and has been credited with saving millions of lives worldwide. 

In 1965, Freireich and his NCI friend and collaborator Tom Frei, M.D., were recruited by MD Anderson to launch a chemotherapy program. Until then, the cancer center had treated patients with surgery and radiation. The two doctors
formed the Department of Developmental Therapeutics and hired brilliant young scientists who developed drug combinations that cured various cancers based on the same methods used to treat childhood leukemia. Today, nearly all successful chemotherapy regimens use this approach of administering multiple drugs simultaneously.

Targeted Therapy

John Mendelsohn, M.D., professor of Genomic Medicine and director of the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy

While the 1970s and ’80s continued to see progress arising from innovations in surgery, radiation and chemotherapy, as well as bone marrow transplantation, the late 1990s ushered in the era of targeted therapies — drugs and other agents like antibodies that interfere with specific molecules found inside of and on the surface of cancer cells, effectively blocking its growth.

Unlike chemotherapy’s random blast, which kills both healthy and cancerous cells, targeted therapies, also called precision medicines, act like a sniper shot aimed precisely at the growth signal in malignant tumors. Targeted therapies usually are not cures, but they stop tumors from growing and spreading, which is significant, because it’s a tumor’s ability to reproduce and metastasize throughout the body
that makes it deadly. By stopping cancer growth, targeted therapies often work in combination with other treatments, such as surgery, chemotherapy or radiation, to effectively remove, shrink or destroy tumors.

The advent of targeted therapy saw the creation of precision drugs by scientists worldwide, including rituximab (Rituxan), which targets certain forms of lymphoma and leukemia; imatinib (Gleevec), for the treatment of certain leukemias, skin cancers, and stomach and digestive system cancers; and trastuzumab (Herceptin), which targets the product of a gene in breast cancers.

One of the very first targeted drugs, cetuximab (Erbitux) was born from research conducted by John Mendelsohn, M.D., and Gordon Sato, Ph.D., while they were faculty members at the University of California, San Diego. Mendelsohn would later become president of MD Anderson, which under his leadership in the early 2000s, became the leading trial site for smart drugs that target cancers at the molecular level. Today, Erbitux is used for colon, pancreatic, head and neck, and lung cancer.

Simply put, here’s how it works: Many cancer cells have receptors called epidermal growth factor receptors (EGFR) on their surfaces. A protein produced naturally in the body called epidermal growth factor (EGF) attaches to these receptors. This triggers the cancer cell to grow and divide into more cancer cells. Erbitux works by attaching itself to the EGF receptors and turning them off by preventing them from binding to EGF.

Mendelsohn likens the process to “putting chewing gum in a car’s ignition to prevent the key from turning on the engine.”

For this discovery, he and Sato are widely acknowledged as the physician- scientists who shaped the landscape for today’s research into targeted therapies.

Mendelsohn says he had the privilege of benefiting from the influence of a number of physicians and mentors early in his career, including James D. Watson, Ph.D., who won the Nobel Prize in Medicine for identifying the structure of DNA. While working toward his bachelor’s degree at Harvard College, Mendelsohn became the first undergraduate student in Watson’s lab.

“The field of molecular biology was in its infancy, ready to explode,” he recalls. “I was introduced into rigorous experimental science and new technologies in a superb scientific environment.”

The past several decades have witnessed a quantum leap in understanding the genetic and molecular causes of cancer, Mendelsohn says, and the pace of drug discoveries is increasing as more abnormal molecular signals and pathways are discovered.

“It’s an exhilarating time to be part of the growing rise of precision medicine,” he says.

Mendelsohn stepped down in 2011 after 15 years of leadership as MD Anderson’s president. He remains on faculty as a professor of Genomic Medicine and director of the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy. The institute focuses on targeting the abnormal genes and products of genes that cause cancer, tailoring specific treatments for individual patients.

“I remain committed to doing what I can to translate the many new scientific discoveries about cancer into better treatments that ease the burden of cancer on our patients today and in future generations.”

Immunotherapy

Jim Allison, Ph.D.

For more than 100 years, scientists and physicians found tantalizing hints that our immune system is capable of detecting, destroying, remembering and permanently stifling cancer, as it does viral or bacterial infections.

In 1891, surgeon William Coley began treating patients with a mixture of bacteria and bacterial fragments called Coley’s Toxins. Coley cured a few patients, but the treatment failed for most and was completely unpredictable. By the early 1900s, it was superseded by radiation, a new therapy with more consistent results.

German scientist and 1908 Nobel Laureate Paul Ehrlich, M.D., proposed that the immune system routinely suppresses tumor formation, a hotly contested hypothesis for decades.

A trickle of immune-related cancer therapies emerged. These included the tuberculosis vaccine Bacillus Calmette-Guérin for non-invasive bladder cancer; an immune signaling molecule, interleukin-2, a harsh drug that helps a small percentage of melanoma patients; and a host of therapeutic vaccines designed to stimulate an immune attack on cancer, which largely failed.

Basic science breaks through

A combination of curiosity-driven basic science research and an intimate familiarity with the personal tragedy of cancer helped Jim Allison, Ph.D., chair of Immunology, lay the foundation for immunotherapy to emerge as the next pillar of cancer treatment.

“I’ve always wanted to know how things work,” Allison says. “I became fascinated with the immune system as an undergraduate, and eventually settled on studying T cells, these remarkable cells that travel all over our bodies detecting and destroying infections and abnormal cells, usually without harming normal cells.”

As a young scientist, he immersed himself and his lab in understanding the basic biology of T cells, first at MD Anderson’s Science Park-Research Division in Smithville, Texas, and later at the University of California, Berkeley.

Allison helped identify a brake on the immune system, an off-switch on T cells that for decades eluded investigators trying to develop immune treatments.

Treating T cells, not cancer

Allison’s key insight was to block the brake with an antibody, freeing T cells to attack cancer.

“I didn’t set out in my research to treat cancer, but it was in the back of my mind,” Allison says. “My mother died of lymphoma when I was 11, and she suffered greatly from the effects of chemotherapy and radiation. An uncle died of prostate cancer, and another of lung cancer.”

His drug treated the immune system, not the cancer, with powerful results in mice.

Given the past failures of immune-based therapies, it took Allison years to persuade a small biotech company to develop the treatment for people. Ipilimumab, a drug developed from his research, became the first ever to extend the survival of patients with late-stage melanoma.

His efforts cleared the way, both scientifically and commercially, for a new class of drugs.

Today, immune checkpoint blockade drugs are approved for late-stage lung, kidney, bladder, head and neck cancers, melanoma and Hodgkin lymphoma; with 15 to 30% of patients responding. Allison’s drug, known commercially as Yervoy, has been in the clinic the longest, and research shows that approximately 22% of late-stage patients live for 10 years or longer — previously unprecedented results.

Hundreds of clinical trials are expanding the reach of these drugs to other cancers and to earlier stages of disease. The answer to higher response rates and longer survival in more cancers, Allison says, is more science.

As executive director of the immunotherapy platform of MD Anderson’s Moon Shots Program™, Allison and colleagues seek to identify new checkpoints to block, and new immune-stimulating molecules to activate and protect. Examination of tumors before, during and after treatment has provided a scientific basis for drug combinations that might make immunotherapy work for prostate, colorectal and other common cancers.

And scientists have developed and are testing new therapies that expand a patient’s own T cells in the lab or genetically modify them to attack specific targets before infusing them back into patients.

“Cancer immunotherapy is still in its early stages, but as science progresses and clinical research grows, we’ll be able to talk about curing or greatly extending the lives of more cancer patients,” Allison says.