Left to right: Salisbury Award Competition judging panel chair Raju Kucherlapati, awardees Jacqueline Douglass and Emily Han-Chung Hsiue, together with NFCR President & CEO Sujuan Ba.
Cancer is a cunning enemy. Not only are there many different types of cancer, but cancer cells closely resemble a patient’s healthy cells, making it difficult to develop new treatments specifically targeting cancer cells without the damaging side-effects associated with traditional cancer therapies.
Johns Hopkins researchers Emily Han-Chung Hsiue, M.D., and MD-PhD student Jacqueline Douglass, Ph.D. in the Vogelstein/Kinzler Lab at the Sidney Kimmel Cancer Center have been researching MANAbodies, an immunotherapeutic approach which could be a significant weapon against cancer, bringing doctors closer to a cure.
MANAbodies are bispecific antibodies that target “Mutation Associated Neo-Antigens” (hence, the MANA) that are bound to human leukocyte antigens (or HLA) molecules. “MANAbodies direct the body’s own immune system to target mutations that are present only on the surface of the cancer cell,” explains Dr. Hsiue. “This results in specific cancer cell killing while leaving normal tissues unharmed.”
The National Foundation for Cancer Research recognized Dr. Hsiue and Ms. Douglass’s MANAbodies research with its 2019 “Salisbury Award for Entrepreneurial Translational Research.” This award is given in honor of the Salisbury family which co-founded NFCR, and the winners are selected by a judging committee made up of leading cancer researchers at universities and research hospitals as well as business leaders in the biotech and pharmaceutical sector.
A New Front
The use of sequencing and other genetic tools has shown that not all cancers of any particular type are the same, nor will they respond to just one kind of treatment. Researchers Hsiue and Douglass are exploring a new frontier, focused on making “personalized” treatments that can target the unique features that crop up around particular subsets of cancer. “Our work epitomizes this concept in that MANAbodies target specific mutations that are present on the cancer cell surface,” said Ms. Douglass. “Each patient’s cancer has a unique set of mutations, although some of these mutations—that is, the so-called ‘shared’ mutations—are found in the cancers of many patients.” MANAbodies target these shared mutations, allowing scientists and clinicians to move one step closer toward the goal of precision medicine.
The MANAbodies project was initially envisioned by primary investigator Bert Vogelstein and Andrew Skora, a post-doctoral fellow, in 2011. “There is a huge chasm between a successful laboratory experiment and its translation to a new diagnostic or therapeutic agent. Such translation nearly always requires interactions with industrial leaders who have the expertise needed to overcome the obstacles that lie within this chasm. It is therefore important that young scientists in academia appreciate these challenges and work with industry to make their scientific breakthroughs become breakthroughs for patients. These interactions are precisely what the Salisbury Awards try to encourage,” said Dr. Vogelstein. At the time, the concept seemed nearly impossible as there were so many unknowns to answer and hurdles to overcome. Among the unknowns that needed to be addressed were how to determine which mutations are present on the cancer cell surface, how to identify MANAbodies that are specific to these mutations, and how to best use MANAbodies in a very potent format.
To address these issues, the lab developed a new technology to accurately detect mutations that can be presented on the cell surface. Next, Dr. Hsiue and Ms. Douglass came up with a bispecific antibody format that had high efficacy. And then they had to demonstrate that the antibodies were tumor-specific and would not harm normal tissues. All these challenges took a great deal of work to address and overcome.
One of the holy grails of cancer research has been to figure out a way to target a protein called p53, which is the single most commonly mutated protein in all cancers and traditionally has been untargetable. “We identified a MANAbody specific to the most frequent p53 mutation,” said Dr. Hsiue. “We then converted this MANAbody into the most potent therapeutic format and have been able to show efficacy against cancer cells in a dish and against cancer cells in mice.”
Dr. Hsiue’s and Ms. Douglass’s work has led to a number of revelations that could ultimately prove relevant to the field of immunotherapy as a whole. “We have found, for instance, that algorithms that are designed to predict which mutations are present on the cancer cell surface are frequently unreliable,” said Ms. Douglass. “Also, we have seen that seemingly similar therapeutic formats can vary tremendously in potency. And, as well, we have noted that the way immune cells, specifically T cells, are grown can have a large impact on their ability to induce MANAbody mediated killing.”
Ultimately, Dr. Hsiue and Ms. Douglass are striving to produce a large panel of MANAbodies, each targeting a different mutant protein that may be present on a patient’s cancer cells. Patients could be screened to see which mutations are present on their tumor, after which the corresponding MANAbody or MANAbodies could be used to specifically target and kill their cancer cells.
The Way Forward
Dr. Hsiue and Ms. Douglass are profoundly grateful for the recognition that they received from NFCR. “NFCR is an incredible organization in that it is willing to invest in and promote early stage projects, such as our own MANAbodies,” said Dr. Hsiue. “This award can help attract the investments which could push an idea that never gets out of the lab toward a viable therapy for use in humans.”
Dr. Hsiue and Ms. Douglass also emphasize that the MANAbody project has been a group effort in so many ways, involving tremendous contributions and efforts in their lab and in collaborating labs, as well as with members of other labs at Hopkins and outside institutions. “Without this coordinated effort that combines the expertise of many people, this project would not have been possible,” said Ms. Douglass. “Indeed, the MANAbody project epitomizes the future of science, where the combined efforts of multiple researchers can usher in major advances.”
Representatives of the 16 selected cancer research projects who participated in the Salisbury Award Competition.
For its part, NFCR is also grateful for the opportunity to recognize distinguished work. “We were very pleased to see so many innovative labs and early stage oncology companies competing for the Salisbury Award,” said NFCR President and CEO Sujuan Ba, Ph.D. “This program is designed to identify high-risk, high-impact, and high-reward projects and help accelerate the pace for them to get into clinics faster. Cancer patients can’t wait.”
Since its founding in 1973 by Franklin Salisbury, together with Nobel Prize winner Dr. Albert Szent-Györgyi, NFCR has been a catalyst for many discoveries such as this one conducted in the lab of Vogelstein and Kinzler. In fact, NFCR supported the lab of Bert Vogelstein and Kenneth Kinzler back in late 1990s. NFCR has provided over $385 million of “adventure funding” to groundbreaking scientists, allowing them to discover what they would not ordinarily be able to find from more conventional investors, given the fear of funding the unknown seen in the government and other funding agencies.Congratulating Dr. Hsiue and Ms. Douglass, former NFCR President and CEO, Franklin Salisbury, Jr., recognized how their research is critical to successfully translating basic science research discoveries into new cancer treatments. “I am so pleased that Dr. Hsuie and Ms. Douglass are the recipients of the 2019 Salisbury Award for Entrepreneurial Translational Research,” said Salisbury, Jr. “This epitomizes NFCR’s founding vision to support the combined efforts by doctors and scientists to make possible new approaches of treating cancers possible.”