A Pioneering Journey in Radiation Oncology Inspired by Multidisciplinary Collaboration

From an early age, having grown up in Albany Park on the northwest side of Chicago, Illinois, Ralph R. Weichselbaum's world revolved around sports, a passion he still follows closely today. “When I was young, I played baseball, basketball, and football before focusing on basketball mainly,” he said. However, he had also been exposed to the world of medicine, which was introduced to him by his father, who worked both as a practicing dermatologist and professor at the University of Illinois College of Medicine. Despite his initial lack of interest in the sciences and in medicine—and most of academia, for that matter—his father’s ability to help make a difference and improve the lives of his patients resonated with him and would be the catalyst for his own desire to pursue a career in medicine.

Following his father’s untimely passing, Weichselbaum found himself at a crossroads, unsure of which professional path to take. His father’s legacy reignited a passion within him and enabled him to find a strong sense of purpose in making a difference in the lives of patients. This passion would stick with Weichselbaum and serve as a hallmark throughout his career. “I’m just as excited now as I was the day I started—actually, I am much more excited now,” he said.

For Weichselbaum, being named the 2024 Giants of Cancer Care inductee in radiation oncology reflects a career journey marked by unexpected twists and turns and fundamental achievements. Weichselbaum currently serves as the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology, chair of the Department of Radiation and Cellular Oncology, and co-director of the Ludwig Center or Metastasis Research at the University of Chicago.

Setting The Necessary Foundation

Weichselbaum began his academic journey at the University of Wisconsin–Madison, where he majored in psychology and history, which are 2 subjects he remains passionate about. It was during his under- graduate studies that Weichselbaum truly grappled with the notion of becoming a doctor, as he was eager to investigate alternative career paths. However, upon graduation, with enough credits and prerequisite courses to apply to medical school, Weichselbaum decided to take a leap of faith.

He was accepted into the University of Illinois College of Medicine and went on to begin his first semester soon after. Upon entering medical school, Weichselbaum’s true passion for science and medicine began to blossom, but not without some reluctance at first. “Becoming interested in science, for me, was an acquired taste when I was much older,” he said.
As he continued developing and honing his interests in the fields of biology and chemistry, he soon found a deep passion for cancer research. During his time in medical school, Weichselbaum was fortunate to work in the laboratory under the guidance of surgical oncologist Tapas Das Gupta, MD, PhD, DSc. This experience ignited his passion for science, culminating in his first publication in Nature.

Following a research fellowship in surgical oncology after earning his medical degree in 1971, Weichselbaum completed his residency at the then-named Harvard Medical School’s Joint Center for Radiation Therapy in 1975 in Boston, Massachusetts. He completed a second fellowship at the John B. Little Center for Radiation Sciences at the Harvard T.H. Chan School of Public Health. After completing this fellowship, he accepted a faculty position at Harvard Medical School, remaining there as a faculty member until 1984, when he reached the rank of associate professor in the Department of Radiation Oncology.
During this time, he was also jointly appointed as a professor of cancer biology at Harvard. In 1984, he was recruited as chair of the Department of Radiation and Cellular Oncology in the Division of Biological Sciences at the University of Chicago, where he remains to this day.

While a faculty member at Harvard Medical School, Weichselbaum found a mentor and friend in Samuel Hellman, MD, FASTRO, the A.N. Pritzker Distinguished Service Professor Emeritus and former dean of the Division of Biological Sciences at the University of Chicago. Hellman is considered by many to be a pioneer of modern radiation oncology in the United States, and Weichselbaum, as a longtime colleague, credits Hellman’s mentorship with solidifying his career focus in the field of radiation oncology.
“At first, I considered becoming a general internist or a medical oncologist, but my experience at Harvard with Dr Hellman solidified my interest in radiation oncology as a specialty, as well as my interest in the field of oncology as a whole,” Weichselbaum said.

Reflecting on the breadth of his journey in oncology, Weichselbaum emphasizes the importance of building a strong foundation in medicine before choosing a specialty. “I always tell the residents that you first need to learn to be a doctor, then you learn to be an oncologist, and only then do you specialize— whether as a radiation oncologist, medical oncologist, or surgical oncologist. This approach broadened my interests and has allowed me to think beyond the traditional boundaries of radiation oncology,” he said.

Career Collaborations Within The Field of Radiation Oncology

Throughout his career, Weichselbaum has emphasized the importance of multidisciplinary collaboration in the continued development of cutting-edge technology within the field and recalls working closely with medical oncologists, virologists, and other specialists to optimize the capabilities of these advancements.
In 1995, Weichselbaum worked with Hellman to coin the term oligometastasis. Together, they proposed the spectrum theory of metastasis, suggesting an intermediate state between localized, curable cancers and lethal, widespread disease, whereby some patients develop only limited metastatic disease. “There wasn’t much study of it at all then,” Weichselbaum said. “[When we talk about metastatic cancer, it’s not always widely spread]. This is really a way to think about cancer and...cancer therapy.”

This practice-altering concept led to the administration of curative regional therapy for patients with oligometastatic disease. In 2018, Hellman and Weichselbaum published a study that established a framework for the integrated classification and treatment of metastasis, which reinforces the biological basis for curable oligometastatic colorectal cancer. The study demonstrated that tumors originating in the colon or rectum and spreading to 1 or a few distinct sites could often be effectively cured with ablative therapies, such as surgery or targeted radiation. This not only validated their original hypothesis but also identified molecular patterns that could predict which future patients would likely experience long-term benefits from such treatments.
However, their work is far from over, according to Weichselbaum, who went on to describe his long-standing professional relationship with Hellman. “We still talk on the phone about the problem of metastasis almost every day, and [the fact that it still kills most patients],” he said.
Weichselbaum harnessed the power of collaboration in another project that pioneered TNFerade, a radio-inducible form of gene therapy that is now under investigation for spatial and temporal targeting of tumors. The innovative cancer immunotherapeutic consists of a second-generation replication-deficient adenovector that expresses human TNFα. Regulated by the radiation-sensitive promoter Egr-1, Weichselbaum and colleagues hypothesized that intertumoral injection of TNFerade could enhance the local effects of radiotherapy by delivering targeted gene therapy directly to the tumor site.
“The real question we were asking was whether radiotherapy could be combined with gene therapy to achieve spatial and temporal targeting of [tumors with] radiation,” Weichselbaum said.

In collaboration with Donald W. Kufe, MD, a researcher at Dana-Farber Cancer Institute and coauthor on one of the early publications about the agent, Weichselbaum recalled promising early results from a phase 1/2 trial that evaluated the safety and feasibility of TNFerade in soft tissue sarcomas. “This was an adenoviral vector that had to be injected locally, and the results were impressive,” he said.
Despite promising initial results, the treatment’s early commercial venture struggled in its application to treat patients with pancreatic cancer. However, Weichselbaum remains hopeful for its future applications, particularly in genetically engineered T cells. “Recently, I’ve started genetically engineering T cells with my colleague and friend [at the University of Chicago], Adekunle Odunsi, MD, PhD, who is the head of the [University of Chicago Comprehensive Cancer Center]. I’m hoping this will make a comeback in some iteration. We’ll just have to see how that’s going to work out,” he said.

Additional collaboration with famed virologist, Bernard Roizman, ScD, explored the impacts of radiotherapy and genetically engineered herpes simplex viruses (HSV), demonstrating that radiation can enhance viral growth within tumors. This innovative approach holds potential for future cancer therapies and continues to be investigated in clinical trials, such as the phase 1 trial (NCT00157703) exploring oncolytic HSV-1, G207, given in combination with radiation for recurrent malignant glioma, which has demonstrated safety and radiographic responses.

Weichselbaum’s long-standing partnership with Everett E. Vokes, MD, FASCO, has also been a cornerstone of his career in oncology. Vokes, a 2013 Giants of Cancer Care award recipient in head and neck cancer and the John E. Ultmann Distinguished Service Professor of Medicine at the University of Chicago, played a significant role in advancing the treatment landscape. Their collaboration began when Weichselbaum moved to Chicago and challenged conventional treatment methods, particularly in the use of chemotherapy before radiotherapy or surgery. Under Vokes’ influence, they began administering chemotherapy and radiotherapy concurrently, which is a practice that has since proved to be transformative. “Dr Vokes impacted me tremendously in terms of the way I think about cancer,” Weichselbaum said.
Weichselbaum emphasizes the value of multidisciplinary collaboration in his career, highlighting how his professional relationships have shaped his approach to cancer research and treatment. “It’s remarkable that some of my closest collaborators have been Dr Vokes, a medical oncologist; Dr Kufe, also a medical oncologist; and Dr Roizman, a virologist. This underscores the critical role of multidisciplinary collaboration in driving advancements in our work and enhancing patient care,” he said.

A Life and Career Marked by Achievement

Reflecting on his career milestones, Weichselbaum expresses the utmost gratitude for his mentors and colleagues, and for the opportunity to influence patient care in a meaningful way.
In 2018, the American Society of Clinical Oncology (ASCO) honored Weichselbaum with the prestigious David A. Karnofsky Memorial Award, recognizing his outstanding contributions to cancer research, diagnosis, and treatment. This award is one of the highest distinctions in oncology, celebrating a specialist who has significantly advanced the field. Weichselbaum delivered the esteemed Karnofsky Lecture at the 2018 ASCO Annual Meeting in Chicago. During his lecture, “Oligometastasis—From Conception to Treatment,” he shared insights from his pioneering work on oligometastasis and its impact on cancer care.

Additionally, his membership with the National Academy of Medicine (previously Institute of Medicine) began in 1997, and he is also a member of the Association of American Physicians.
Outside of his professional accomplishments, Weichselbaum cherishes his family life, finding great pride and joy in his wife Donna, their 3 sons and daughters-in-law, and their growing number of grandchildren.

Alongside his dedication to medicine, Weichselbaum maintains a strong passion for sports, a keen interest in reading—especially on topics related to modern German and Soviet history—and a deep engagement with current events.
As Weichselbaum reflects on his career, he remains deeply passionate about the evolving landscape of cancer treatment. Looking ahead, he is enthusiastic about the potential of emerging therapies, particularly the integration of targeted therapies, such as immunotherapy, and advanced imaging techniques.
“I would like to see how the concept of oligometastasis continues to play out in clinical practice. I’d like to see how it interacts with the targeted agents and immunotherapy, and how radiotherapy and immunotherapy interact or don’t interact,” he said.
“Some of the imaging is going to change clinical staging. I think these peptides and antibodies labeled with radioisotopes are going to change things, both in terms of finding and killing tumors [as well as] allowing external radiation, chemotherapeutics, and hormones to be used in patients with metastatic disease,” he continued, discussing his hopes for the future of clinical practice.