Michael T. Lotze, MD: To Each His Own Adaptome

Year Funded: 2020-2022

“Our immune system protects us from viruses and bacteria, and it also protects us from tumors,” says Michael T. Lotze, MD, vice chair of research at the University of Pittsburgh School of Medicine Department of Surgery (Pittsburgh, PA). “The issue is it’s not a one-size-fits-all scenario. Every person walking this earth has a uniquely different adaptome, which we also call the adaptive immune system. Mastering the biology of an individual’s adaptome is what will enable us to cure cancer within the next five to 10 years.”

Long regarded as one of the fathers of modern immunotherapy, cell therapy, and gene therapy, Dr. Lotze explains there are four points of study to consider when defining what it is that makes people fundamentally different from each other and understanding why some people develop cancer while others do not.

“First we consider the genome,” says Dr. Lotze. “The genes that individual human beings inherit from their parents are 99.98 percent identical. After that, we see that microbiomes — the aggregate bacteria that reside in people’s guts and on people’s skin as a result of diet and environment — are 95 percent the same from person to person.

“Cancers are caused by a build-up of mutations in a person’s genes. These mutations are what we call the mutanome. How an individual’s immune system responds to these gene mutations is what makes people wildly different. Everybody has their own unique adaptome – the adaptive immune system. Unlike genomes and microbiomes, similarities between adaptomes are a mere three percent from one person to another. Even identical twins are distinctly different with similarities at just six percent.”

T cells are a key component of the adaptome. “There are many different kinds of protective T cells,” says Dr. Lotze. “Everyone has them, but over time as people age, their T cell diversity decreases. Consequences of this diminishing diversity include several immune deficiencies, including cancer.”

At any given time, alpha beta T cells are the most predominant, comprising about 90 percent of all T cells. These T cells are the primary focus of current cancer cell and gene therapies. With funding from Alliance for Cancer Gene Therapy (ACGT), Dr. Lotze and his team are moving beyond alpha beta T cells, further advancing their years of accumulated research knowledge into pioneering the exploration of a less appreciated, less abundant, and less studied class of T cells known as gamma delta T cells.

“Gamma delta T cells within the tumor (tumor infiltrating lymphocytes or TIL) have never been evaluated as a treatment for patients with cancer and we believe they will prove to be part of the ultimate personal and precision medicine,” says Dr. Lotze. “We will take these naturally protective gamma delta T cells from a patient’s pancreatic tumor, grow them into an army and return them to that patient to find and destroy that specific tumor. They will then couple with other cells within the patient’s unique adaptome, providing the power it needs to destroy the cancer.”

Four important publications document milestones in Dr. Lotze’s journey to this new approach to cancer treatment and a suitable turning point. The first was published in Cancer Research in 1981; the second in the Journal of Experimental Medicine in 1996; the third in Cell Metabolism in 2010; and most recently, the fourth in Clinical Cancer Research in 2020.

Dr. Lotze’s distinguished career has always been predicated on the bench-to-bedside-to-bench paradigm in science. Well known for development of the drug interleukin 2 (IL-2) for melanoma and kidney cancer, he compares his 40 years of progress with the Matryoshka, Russian nesting dolls. “I’ve had the great opportunity to work with some extraordinary individuals who, like me, were intrigued by the complexity of the immune system’s role in responding to cancer,” says Dr. Lotze. “Inch by inch, layer by layer, the deeper we dig, the more we reveal the underlying principles of life, cancer, biology and immunology.

“Since the day it was founded, ACGT has been committed to achieving a better understanding of cancer biology and immunology, translating that understanding into game-changing clinical therapies. This is exactly what we expect our current ACGT-funded research to achieve.”

“The advances that have been supported by ACGT are ushering in a whole new era of cancer therapies — safer, more effective, and with long-term benefits. We now know enough about cancer and immune responses that we can make smart choices for how to combat the disease.”

Dr. Lotze earned an MD and BMed Sciences through the Honors Program in Medical Education at Northwestern University (Evanston, IL). Since he launched his career in the Surgery Branch of the National Cancer Institute (Bethesda, MD), he has led high-impact investigations and fostered global collaborations among like-minded researchers. His many achievements are documented in more than 500 peer-reviewed publications and 10 patents.

Personal Quotes

“Since the day it was founded, ACGT has been committed to achieving a better understanding of cancer biology and immunology, translating that understanding into game-changing clinical therapies.”

“The advances that have been supported by ACGT are ushering in a whole new era of cancer therapies — safer, more effective, and with long-term benefits. We now know enough about cancer and immune responses that we can make smart choices for how to combat the disease.”

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