There are more than 25 cancer immunotherapies on the market right now—5 of which were approved in 2014 alone. There are cytokines that boost the immune response, monoclonal antibodies designed to target antigens on cancer cells, preventive and therapeutic cancer vaccines, and immune checkpoint inhibitors.
But what—in its 60+ years as an organization—did the Cancer Research Institute (CRI) contribute? Quite a lot. Let’s look.
Interferon alpha (IFN-α)
Interferon alpha (IFN-α), a cytokine that is responsible for regulating and activating the immune response, was the first cancer immunotherapy approved by the FDA in 1986. It had been tested since the late-1970s, when CRI provided seed funding for the first significant clinical trial of IFN-α in human cancer patients, conducted by Jordan U. Gutterman at MD Anderson Hospital and Tumor Institute (now MD Anderson Cancer Center). This was the first human testing of a biological therapy for cancer ever. The FDA approved the cytokine in 1986 for hairy cell leukemia, and later for chronic myelogenous leukemia (CML), follicular non-Hodgkin lymphoma (NHL), melanoma, and AIDS-related Kaposi’s sarcoma.
“The award during the past year of $12,000 by the Cancer Research Institute to me for interferon studies has been extraordinarily important to me in getting the initial work off the ground.” – Jordan U. Gutterman, Letter to Helen Coley Nauts, September 13, 1978
Bacillus Calmette-Guérin (BCG)
The second immunotherapy approved was Bacillus Calmette-Guérin (BCG) in 1990. It was Lloyd J. Old, in partnership with Baruj Benacerraf and Donald Clarke, who demonstrated that BCG, the tuberculosis vaccine, could inhibit tumor growth in mice, in 1959. In 1975, CRI funded Alvaro Morales, of Queens University in Canada, who demonstrated that BCG is effective in the prevention of recurrence of non-muscle invasive bladder cancer. The FDA approved the use of BCG for superficial bladder cancer in 1990. CRI bestowed the William B. Coley Award on Morales in 1993.
“In the early 70s my rejection by the National Cancer Institute of Canada to test Bacillus Calmette-Guérin (BCG) on superficial bladder tumors included the reviewer comment ‘BCG is not only ineffective and dangerous but a throw back from the stone age of tumor immunology.’ If I hadn’t subsequently applied to and been approved for a grant from CRI, BCG might never have become the standard therapy for the treatment and prevention of early stage bladder cancer.” – Alvaro Morales
Herceptin® (trastuzumab) was the second monoclonal antibody to be approved in 1998 (the first was Rituxan® (rituximab) in 1997). Mien-Chie Hung, a CRI postdoctoral fellow from 1983 to 1986, was one of the first three to clone the HER2/neu oncogene, a key milestone enabling the development of trastuzumab and other HER2-directed therapies for HER2+ breast cancer .
The cervical cancer vaccine, Gardasil®, was developed by Ian H. Frazer. In 1999, the Cancer Research Institute awarded the first of several grants to Frazer for work on virus-like particles (VRP)-based papillomavirus vaccines, which he credits with the development of Gardasil. In 2006, the FDA approved Gardasil, which now protects against nine types of HPV that cause approximately 90% of all cases of cervical cancer worldwide. CRI presented its William B. Coley Award to Frazer in 2006.
“This new vaccine that prevents cervical cancer grew out of research funded by CRI.” – Professor Ian Frazer
After completing his CRI postdoctoral fellowship at Stanford University in 1993, Curtis L. Ruegg joined Dendreon as a staff scientist. In 1995, he established the protein science group and led Dendreon’s program to produce and characterize novel protein pharmaceuticals as cancer vaccine candidates. His work resulted in several patents on which he is co-inventor, which laid the key groundwork for the development of Provenge® (sipuleucel-T) . Provenge was the first therapeutic cancer vaccine approved by the FDA in 2010 for prostate cancer.
In 1997, CRI investigator award recipient Yongwon Choi and colleagues discovered the TRANCE protein (now known as RANKL). This protein is the key target of the monoclonal antibody Xgeva® (denosumab), which was approved by the FDA in November 2010 for the prevention of fractures and other skeletal-related injuries in patients with cancers that have spread to the bone. Because bone metastases occur in more than 80% of patients with advanced prostate cancer, this new treatment may help significantly improve quality of life for men with the disease. This treatment may also benefit patients with advanced breast and lung cancers, in which bone metastases are also common.
In 1996, when James P. Allison published his—now famous—paper in Science, “Enhancement of Antitumor Immunity by CTLA-4 Blockade,” he cited the work of five CRI scientists, and five on his patent. These include Jane A. Gross (1991-1994 CRI postdoctoral fellow) and Fiona A. Harding (1992-1993 CRI postdoctoral fellow) who worked with him as postdoctoral fellows. This work led to the checkpoint blockade inhibitor Yervoy® (ipilimumab), which was FDA approved in 2011. This was the first treatment ever shown to extend the lives of patients with advanced melanoma.
Setting the stage for combining Herceptin® (trastuzumab) and Perjeta® (pertuzumab), in 2005, Yosef Yarden, a 1987 CRI postdoctoral fellow, first demonstrated in the laboratory that combining trastuzumab with an antibody directed against a different part of HER2 is more effective than trastuzumab alone against HER2+ breast cancer.
We funded the work of three scientists—Arlene Sharpe, Gordon Freeman, and Lieping Chen—whose research was crucial in establishing PD-1 as a new checkpoint that could be targeted with immunotherapy. More recently, Antoni Ribas, at UCLA, who is a member of our clinical trials network and a CRI-SU2C Dream Team Co-Leader, Jedd Wolchok, CRI Trials Network director, Hassane Zarour, CRI Trials Network member, and F. Stephen Hodi, CRI Trials Network member, were investigators of the trial that established the drug’s efficacy.
Micromet (now Amgen), building on the work of Gert Riethmüller, a CRI Scientific Advisory Council member, developed a bispecific T cell engager (BiTE) designed to target the CD19 antigen on B cell leukemia and the CD3 antigen on T cells, effectively using the T cells to kill the leukemia cells. Riethmüller was also involved in the clinical testing of the drug, as was Max S. Topp, a former CRI postdoctoral fellow and now a professor at Würzburg University Hospital in Germany. Topp was the first author on the phase I publication and the phase II American Society of Clinical Oncology abstract that showed that blinatumomab has anti-leukemia activity in this difficult-to-treat population.
For more achievements, visit Our Accomplishments or Timeline, an interactive chronology of the field of cancer immunology and immunotherapy.
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