How Targeting a Rare Blood Cancer Complication and Bacteria in Colorectal Cancer Can Bolster Immunotherapy Outcomes

Immunotherapy triggers the body’s immune system to effectively and precisely respond to cancer. However, immunotherapy is not a one-size-fits-all scientific discipline—even two patients with the exact same cancer might require different treatments based on a variety of factors. The Cancer Research Institute (CRI) funds dozens of scientists whose research covers a chasm of scientific ground. This includes niche focuses such as Richter’s Transformation Syndrome (RT), a condition that occurs when chronic lymphocytic leukemia (CLL) morphs into a more aggressive cancer, or more broad areas like how immunotherapy interacts with a tumor’s bacteria in colorectal cancer. 

Julio Delgado, MD, hematologist at the Institut d’Investigacions Biomèdiques August Pi i Sunyer in Spain and CRI Clinical Innovator, is investigating how immunotherapy can help RT patients, while Jorge Luis Galeano Niño, MD, PhD, assistant professor of biological sciences at the University of Texas at El Paso and CRI Postdoctoral Fellow, is determined to discover novel tumor-associated antigens rooted in bacterial species that live in colorectal patients’ tumor tissue.  

“The world of cell therapies, and advanced therapies in general, is one in which academic institutions can be very competitive,” Dr. Delgado told CRI recently in discussions about both National Hispanic Heritage Month and his research. “Our main goal is to provide these potentially life-saving cell products to every patient in need, regardless of their race, origin, or wealth.” 

Drs. Delgado and Galeano Niño spoke with CRI about how to address disparities in cancer treatment and care for the Hispanic community. They also elaborated on their specific avenues of cancer immunotherapy research, including obstacles and areas of promise for the future.

What is RT, and How Does it Relate to Blood Cancers?

“RT occurs as a terrible, and often lethal, complication in patients who already suffer from CLL.”

Julio Delgado, MD, CRI Clinical Innovator

RT is a rare syndrome that morphs CLL into Hodgkin or diffuse B cell lymphoma. Symptoms include fever, rapidly enlarged lymph nodes, abnormalities in electrolytes, and fatigue. The root cause for RT is not yet established, which is all the more reason for the scientific community to highlight and further research this disease.  

Dr. Delgado will lead a pilot study called RICHARDIII, part of a larger trial called CARTD-BG-01 in which a novel chimeric antigen receptor (CAR) T cell called ARI-0003 targets multiple proteins that are expressed in lymphoma cells. CAR T cell therapy is a type of adoptive cellular immunotherapy engineered to harnesses the immune system’s killer T cells to bind on the surface of cancer cells—he said this new CAR T cell therapy might be capable of curing a significant proportion of RT patients. 

“The treatment of several types of lymphoid leukemia and lymphoma has greatly improved in the last five years with the advent of CAR T cell therapy,” Dr. Delgado explained in conversation with CRI. He has published multiple scientific research papers in the past year about both CLL and CAR T cell therapy for lymphoma patients. “Unfortunately, half of our patients treated with our original product, ARI-0001, experienced disease relapse and half of these patients lost CD19 expression in their tumor cells. By targeting two antigens, CD19 and CD269, we hope to prevent these CD19-negative relapses.” 

Dr. Delgado and other CRI-funded scientists focused on immunotherapy for blood cancers are on the frontlines of the battle against these terrible malignancies. A large portion of his current research is designed to identify illusive immunotherapy targets expressed exclusively on tumor cells. This discovery could prove crucial for RT patients and others with blood cancers. 

Does Bacteria Hold the Key to Unlocking Effective Colorectal Cancer Immunotherapies?

“Since bacteria antigens can be expressed by cancer cells, this opens the possibility to develop new immunotherapies aiming to eliminate infected cancer cells using T cell-based therapies.”

Jorge Luis Galeano Niño, MD, PhD, Postdoctoral Fellow

Colorectal cancer is extremely common—about 1.8 million people are diagnosed annually with the malignancy worldwide, and it is the third most common and second most fatal cancer in the U.S. Symptoms include abdominal pain or cramping, weakness or fatigue, and diarrhea or constipation that lasts for days.

Dr. Galeano Niño said in conversation with CRI that the future of colorectal cancer immunotherapy should focus on improving tailored treatment and safety for patients since current treatment targets self-antigens that are overexpressed in tumor cells. Self-antigens are receptors or protein molecules on the surface of cells that tell the immune system a cell is a normal part of the body and not a foreign pathogen. Cancer cells can cloak themselves from immune system detection as they also express the same self-antigens albeit sometimes in larger quantities.

“For instance, the development of synNotch CAR T cells allowed the elimination of cancer cells that express simultaneously two tumoral antigens, increasing specificity,” he said. The synNotch receptor can recognize a specific priming antigen and can enable precise tumor cell elimination. “The screening of tumor-associated antigens such as bacterial ones that are expressed in cancer cells in the context of human leucocyte antigen (HLA) molecules can be used to develop more specific immunotherapies. Bacteria mostly produce foreign antigens that are not related with the host.” HLA molecules are proteins located on most cells in the body, and they help the immune system identify normal cells from invasive ones. 

Improved detection methods have caused the colorectal cancer mortality rate to decline over the past couple of decades—the five-year survival rate stands at 90 percent when it is caught early. While this is a promising trend, Dr. Galeano Niño and other colorectal cancer immunotherapy scientists implement thoughtful, precise research in the hopes of curing this prevalent disease. CRI is funding colorectal cancer immunotherapy research that explores multiple avenues to find new treatment modalities for this deadly disease. Notable research efforts involve the immune checkpoint blockade activation, which involves taking the ‘breaks’ off the immune system so immunotherapy can robustly attack cancer cells, or identifying the regulators of interactions between malignant and immune cells. 

Niche and Wide Research Scopes for Unmet Medical Needs 

Just like cancer treatment, immunotherapy research is a science that involves tailored approaches for different segments of patients. While Dr. Delgado’s research addresses a rare condition affecting blood cancer patients and Dr. Galeano Niño’s research focuses on bacteria’s role in a very common cancer, both are crucial towards the goal of developing a cure for these malignancies.   

Dr. Delgado is hopeful that his efforts will develop the best possible product for his patients both in terms of efficacy and safety. He told CRI, “A big portion of current research with blood cancers is focused on the identification of a target that is expressed exclusively on tumor cells, and I am therefore hopeful many things will change in the near future.” Dr. Delgado emphasized his desire for the RichardIII study is to contain a prolonged patient response and create a curative treatment for RT patients. 

With colorectal cancer, a challenge to further progress is that there are dormant cancer cells within tumor tissue where bacteria reside, and they ‘wake up’ and can lead to recurrence and relapse. Dr. Galeano Niño expressed that if cancer researchers can better understand the molecular mechanisms by which intratumoral bacteria regulate the immune response in tumor tissue, they will be able to help more colorectal cancer patients by reducing inflammation and enabling improved T cell activity. 

Both Drs. Delgado and Galeano Niño conduct research with the aim of helping more cancer patients whose cancer prognoses would benefit from improved immunotherapy treatments. CRI is grateful for their time and their research, both of which bring us closer to a world immune to cancer.