Researchers detail new findings at 2019 AACR meeting

March 28, 2019 | by Zen Vuong

Michael Caligiuri, M.D.

City of Hope will showcase ongoing studies and data on chimeric antigen receptor (CAR) T cell therapy, immunotherapy against solid tumors and more at the American Association for Cancer Research (AACR) annual meeting from March 29 through April 3 in Atlanta.

More than 22,500 scientists, advocates and clinicians from around the globe are expected to attend the 2019 AACR meeting at the Georgia World Congress Center to discuss the latest advances in immunotherapy, artificial intelligence, targeted therapy, liquid biopsy, science policy and cancer health disparities.

“City of Hope’s physicians and scientists will share their discoveries and leading-edge expertise with colleagues in the cancer field,” said Michael Caligiuri, Deana and Steve Campbell Physician-in-Chief Distinguished Chair, president of City of Hope National Medical Center and former AACR president.

Highlights of City of Hope’s significant contribution to discovering breakthroughs in cancer diagnosis, prevention and treatment include the following:

Immunotherapy arsenal: Ecology of the tumor microenvironment in breast cancer

To destroy a tumor, physicians shouldn’t just target the cancer cells, said Peter P. Lee, M.D., Billy and Audrey L. Wilder Professor in Cancer Immunotherapeutics at City of Hope. Doctors should also develop treatments that target or alter the tumor microenvironment. “Think of the tumor microenvironment as an ecosystem or a game of Jenga,” Lee said. “The building blocks of a tumor comprise not just cancer cells, but also support (stromal) cells, immune cells, as well as an extracellular matrix. If you target any of the critical building blocks that support the cancer cells, you would still be able to get the tumor ecosystem to collapse.”

For the past three years, Lee has led a convergent science team to study the Ecology of the Tumor Microenvironment in Breast Cancer through the support of Stand Up to Cancer. His team of biomedical scientists, physician-scientists, physicists, mathematicians and computer scientists has generated petabytes of data about the impact of the spatial interplay between components of the tumor microenvironment on disease progression. They have published papers in Nature Communications and the Proceedings of the National Academy of Sciences; they are currently working on several additional manuscripts.

How population differences and environmental exposures affect tumor biology

Scientists are beginning to learn how environmental exposures like culture and individual life choices influence the biology of tumors and specific cell mechanisms. Research shows that more aggressive tumors with worse prognoses are sometimes the result of population differences and increased exposure to disease risk factors. Rick A. Kittles, Ph.D., associate director of Health Equities at City of Hope’s comprehensive cancer center, will discuss an ongoing study that looks at the role of vitamin D in prostate cancer. He will elaborate on how vitamin D intake can serve as a biomarker for prostate cancer risk. Victoria L. Seewaldt, M.D., Ruth Ziegler Chair in Population Sciences at City of Hope, will discuss breast cancer and how health disparities can result in obesity and inflammation, both of which improve the chance of incurring aggressive tumors in the breast.

How global health research advances cancer health equity in the U.S.

Rick A. Kittles, Ph.D., director of the Division of Health Equities at City of Hope, and other scientists will discuss how global efforts to eliminate cancer contributes to the advancement of cancer health equity in the United States. Kittles will explore the impact different environments have on genes. In particular, he will talk about the African diaspora, which moved millions of people from western and central Africa to the Americas and the Caribbean. Genetically, these individuals are not very different, but different environmental and social experiences across the lifespan resulted in varied disease susceptibility and health outcomes.

Natural killer cells

Michael Caligiuri, M.D., president of City of Hope National Medical Center and former AACR president, will detail natural killer cells and the findings his scientific teams have made in the past 25-plus years in this field. His research in natural killer cells and other topics led the AACR Academy to induct Caligiuri as a fellow last year to recognize his significant scientific contributions that have propelled consequential innovation and progress against cancer.

The protein CD27+ may mark just how effective CAR T cell products are

City of Hope researchers continue to make headway in developing more efficient CAR T cell treatments and are using a new preclinical study finding to try to refine its ongoing clinical trial of CAR T cell therapy against glioblastomas. Dongrui Wang, a Ph.D. candidate at the institution, Christine Brown, Ph.D., Heritage Provider Network Professor in Immunotherapy and associate director of the T Cell Therapeutics Research Laboratory at City of Hope, and others found that the immune T cell surface protein CD27 makes CAR T cells better tumor killers through interaction within its signaling molecule CD70. Specifically, CAR T cells enriched for CD27+ cells exhibited enhanced memory function and were able to perform their antitumor activity longer both in vitro and in vivo. “This study is a big step toward refining our CAR T cell manufacturing processes: We should preserve the CD27+ population to magnify the immunotherapy’s therapeutic applications,” Wang said. “Our study also suggests that CD27+ can be used as a biomarker to predict how effective and potent an immunotherapy will be in specific patients in City of Hope’s clinical trials.”

The glioblastoma clinical trial Wang referenced earlier opened in 2015 and is a part of the California Institute for Regenerative Medicine-sponsored City of Hope Alpha Stem Cell Clinic.

Combining engineered autologous T cells with a monoclonal antibody to treat solid tumors in advanced lung cancer

Leading the path into the next stage of immunotherapy, City of Hope is enrolling patients in an autologous T cell clinical trial that aims to re-engineer and use a patient’s own immune T cells to attack solid tumors in the body. Enhanced T cell therapy has been successful in treating hematologic (blood) cancers and is in early development for solid tumors.

The randomized 1a/2b study will investigate the safety and efficacy of enhancing a patient’s own T cells with NY-ESO-1/LAGE-1a antigens so that his or her immune system will better attack advanced nonsmall cell lung cancer. The therapy, of course, can be used only in people whose tumors express the NY-ESO-1 and/or LAGE-1a receptors.

Today’s standard of care for advanced nonsmall cell lung cancer leads to long-term benefits for about 10 percent of patients, said Karen Reckamp, M.D., M.S., co-director of the Lung Cancer and Thoracic Oncology Program at City of Hope and principal investigator of the ongoing clinical trial. The majority of patients with this disease have few treatment options. “T cell therapy is a high priority for City of Hope,” Reckamp said. “We hope to move enhanced T cell therapy forward in solid tumors, especially in lung cancers.”

In the ongoing clinical trial, the patient’s engineered T cells, called GSK3377794, will be used alone and in combination with pembrolizumab, a monocolonal antibody that blocks PD-1/PD-L1 interaction and increases the antitumor function of T cells. The synergistic treatment potentially can help certain patients with Stage 3 or Stage 4 nonsmall cell lung cancer — people who have tried other treatments but have not been able to find their way back to health.

The study is a part of the California Institute for Regenerative Medicine-sponsored City of Hope Alpha Stem Cell Clinic. It is supported by GlaxoSmithKline and is a collaboration with Merck & Co. Inc.

Moving diagnostic technology into today’s world using artificial intelligence and 3D imaging

City of Hope and its affiliate Translational Genomics Research Institute (TGen) is collaborating with others to create the future of oncologic radiology — what City of Hope’s Syed Rahmanuddin, M.B.B.S., calls “the mammogram of pancreatic cancers.” His team is using top-of-the-line technology to create artificial intelligence algorithms that compile a detailed 3D image of pancreatic cancer. The purpose is to enable physicians to identify the volume of blood flow (perfusion kinetics) of tumors and learn how effective a treatment is, facilitating adjustments to regimens to allow for improved targeted cancer therapy. Right now, the standard of care is flat, black-and-white multiphase computed tomography (CT) imaging. “Our new, patient-centered 3D imaging approach is like the transition from thinking the world is flat to understanding that the world is a globe: It opens up a whole world of possibility,” Rahmanuddin said. “Our pilot study suggests that change in 3D volume and perfusion (blood flow) are important imaging markers that correlate with tumor progression, regression and aggression, which could be very helpful for the early detection of pancreatic cancer.”

Daniel Von Hoff, M.D., physician-in-chief and distinguished professor of TGen, and Ronald Korn, M.D., Ph.D., of Imaging Endpoints, were key contributors to this research.

Molecule found in orange peel slows down breast cancer tumor growth in mouse models

A molecule found on the skin of citrus fruits appears to inhibit the growth of breast cancer tumors in a mouse model. Compared to control mice with xenografted breast cancer cells, those who received 2’-Hydroxyflavanone (2HF) experienced reduced viability and proliferation of breast cancer cells. In addition, 2HF inhibited the expression of RLIP, a protein that is overexpressed in breast cancer cells. “While more research is needed to see if what we found in our mouse models can be translated to human subjects, it is important to note that natural compounds extracted from, say, orange peels is not toxic and has been shown to be beneficial, including lowering glucose triglycerides and cholesterol levels,” said Sharad Singhal, Ph.D., lead author of the study and research professor in medical oncology at City of Hope. “In the distant future, it’s possible that 2HF supplements can be taken by breast cancer patients to enhance the effectiveness of medical treatment.”

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