A new tumor immunology computational tool created by USF medical student Boris Chobrutskiy may help improve the predictability and precision of cancer immune therapies. He is first author of a study recently reported in Oncogene.

3D-rendered illustration of T-cells of the immune system attacking growing cancer cells

In the last decade, several immunotherapy drugs have been approved that rev up the patient’s own immune system to selectively combat cancer. These revolutionary anticancer treatments have shown remarkable potential to prolong the lives of those with malignant melanoma, advanced lung cancers and other types of cancers – but not all patients benefit equally. Their widespread use has been limited by unpredictable response rates and autoimmune side effects, including occasional life-threatening inflammatory damage.

Researchers at the USF Health Morsani College of Medicine’s Department of Molecular Medicine study the complex interplay between tumors and immune cells. They wanted to better understand apparently contradictory reports about the positive and negative effects of immune response in low-grade gliomas (LGG), brain tumors that grow slowly but are deadly.

So, they used the federal genomics database The Cancer Genome Atlas and a sophisticated computational method developed by third-year USF Health medical student Boris Chobrutskiy to determine the chemical match (complementarity) between a type of immune cell known as T lymphocytes (T-cells) and tumor-specific antigens. In particular, they delved into how well patient-specific T lymphocyte receptors matched abnormal proteins (antigens) of the patient’s LGG tumor cells. These tumor antigens flag the immune system to recognize and attack the tumor cells as “non-self” invaders so they do not grow uncontrollably.

Based on Chobrutskiy’s chemical complementarity scoring system, the researchers found that patient survival rates significantly increased when LGG-associated immune cell receptors (specifically the amino acid sequences of complementarity-determining region-3, or CDR3) were a good match with the cancer’s mutated protein, a tumor antigen known as the isocitrate dehydrogenase-1 (IDH1) mutant. Of 100 patient cases scoring high matches, 80% of the patients were living more than five years following diagnosis. Conversely, for 158 patient cases with poor or no discernable matches, only 30% survived beyond five years.

The USF Health study, with Chobrutskiy as lead author, was reported recently in the high-impact journal Oncogene. The paper’s senior author George Blanck, PhD, USF Health professor of molecular medicine, said Chobrutskiy’s latest publication is “a potential game changer” for developing next-generation tumor immunology tools. It is the medical student’s 16^th peer-reviewed article with faculty mentor Dr. Blanck and other co-authors in the molecular medicine group.

Third-year USF Health medical student Boris Chobrutskiy with research mentor George Blanck, PhD, a professor of molecular medicine

“Boris’s big accomplishment — both a thought success and a computer programming success — was figuring out how to track down matches between the mutant protein in the cancer and the receptor on the T-cells (lymphocytes). “It’s like finding two matching needles from two different haystacks,” Dr. Blanck said. “He was able to bring the chemistry of what’s happening in the body (with cancer-immune cell interactions) into the computer.”

Computational models like the one created by Chobrutskiy could improve the reliability of prognoses for LGG and other cancers — that is, the ability to predict whether existing checkpoint inhibitors or other cancer immune therapies will benefit a patient, Dr. Blanck said. “That could save a lot of patients from a potentially harsh reaction to an immunotherapy that does nothing for them.”

Clinicians already know that the absence of an IDH1 mutation represents a poor prognosis for LGG. However, the USF Health researchers suggest, a scoring system like Chobrutskiy’s, that can distinguish how effectively the immune receptors complement the IDH1 mutants, adds prognostic value and may help guide therapy for those patients who do carry the mutation.

Ultimately, advanced technologies characterizing cancer immunity could also be used to develop more precise therapies to kill targeted tumor cells while sparing healthy cells, preventing the extensive inflammation caused by an immune system in overdrive, Chobrutskiy said. “It’s an opportunity to personalize treatment for both a patient’s cancer with its unique mutations that drive tumor growth, and for the patient’s particular lymphocyte (T cell) repertoire.

Unlike other immune cells with largely genetically identical receptors, every mature lymphocyte has a unique receptor on its cell membrane. When an antigen invades the body, normally only those lymphocytes with receptors that best fit the contours of that particular antigen mount the immune response. This receptor diversity enables the lymphocyte to recognize and bind hopefully at least one antigen, whether the invading pathogen is a bacteria, virus, or cancer cell.

Chobrutskiy harnessed the power of Big Data and created an algorithm to track down  matches between the mutant protein in the cancer and the receptor on the immune cells. “It’s like finding two matching needles from two different haystacks,” Dr. Blanck says.

Since we have so many unique lymphoctyes and no two tumors are alike, “you really need a computer tool to sift through all the data and do the chemistry and math calculations to figure out the best matches,” said Chobrutskiy, who does computer programming as a hobby. “Finding the matches (between immune receptors and tumor mutants) in the laboratory would be way too expensive and time-consuming with such a large number of samples.”

The USF Health researchers will next test their hypothesis that patients with LGG who respond well to checkpoint inhibitor drugs will be those with highly specific binding interactions, or the “best fits,” between their immune cell receptors and tumor mutants.

“We know that their immune systems are already poised to go, whereas in the patient with no match, it doesn’t matter how well the T-cell works or how much you ‘uninhibit’ the T-cell,” Dr. Blanck said. “There’s nothing for the T-cell to do, because without a match even a boosted immune system cannot get rid of the cancer.”

The study was supported in part by USF Research Computing and MCOM Research, Innovation & Scholarly Endeavors fellowships.

-Photos by Freddie Coleman, USF Health Communications and Marketing

Science is full of precision and vigilance. But sometimes, there are subtleties that present themselves that get ignored, pushed aside for the drive to stay on task or to stick with the parameters of a hypothesis.

Michele Parry, a student in the Masters of Molecular Medicine Pre-Professional Program at the USF Health Morsani College of Medicine, was working for the former when she experienced the latter. It was an “ah ha!” moment that ended up being a key finding for why certain genes of cancer cells mutate, while others don’t.

Michele Parry.

Parry volunteered in the lab of George Blanck, PhD, professor of molecular medicine, who was studying how the size of a gene’s protein coding region affects it’s the likelihood of becoming mutated. While combing over screen after screen of data – spreadsheets, graphs, and countless lists – she spotted a trend: larger genes are more frequently mutated than smaller ones, and in particular genes encoding cytoskeletal proteins.

“She spotted something that I didn’t and, thanks to that, we were able to run with it,” said Dr. Blanck, whose work looks into the nuances of genes and who pushes to fill the pipeline with talented biomedical sciences students.

The gene mutation work warranted publication, for which Parry was first author. It’s unusual for master’s students to be first author of published research, but Parry’s story is a good example of the experiences students in the USF master’s program can have, Dr. Blanck said.

“This is what master’s students in our program can do,” Dr. Blanck said.  “The role of the student in research is becoming more apparent. Nurturing that experience for a student researcher is directly connected to our mission of teaching.”

Titled “Big genes are big mutagen targets: A connection to cancerous, spherical cells?” in the September 2014 edition of Cancer Letters – the publication resulted in funding for new research looking into how the shape of cancer cells (round versus flat) affects drug resistance.

Dr. Blanck and Wade Sexton, MD, associate professor in the USF Department of Oncologic Sciences and a bladder cancer specialist at Moffitt Cancer Center, were awarded the Anna Valentine Award by Moffitt Cancer Center for new work titled “Cytoskeletal protein related coding region mutations in bladder cancer.”

“Cancers cell have unique characteristics and their shape may affect whether or not they are resistant to drugs,” said Parry.

Parry has a bachelor’s degree in biology and wants to be a physician. Specifically, she wants to be an oncologist. She’s driven to understand the difficult science and realizes she’s lucky to pick it up so fast.

“I’m happy that I’m educated and can understand a lot of this,” she said. “And tutoring the master’s students really helps me cement the molecular biology concepts. We’ll see if I feel the same way as a medical student.”

Parry applied to medical school once and was told to strengthen her resume to increase her likelihood of acceptance.

So, strengthen it she did. Since first applying to medical school in 2012, she has graduated with her master’s degree earning a 4.0 GPA, she now works in Dr. Blanck’s lab and has been published as first author, she is an adjunct professor at St. Petersburg College, and she is the graduate teaching assistant for the master’s program.

“This was supposed to be my year off,” she joked. “But I needed to do all of this to strengthen my candidacy and to prove I could excel at the graduate level.”

Was that “ah ha!” moment proof of her abilities? Parry describes it more as a chance to contribute to promising cancer research.

“It makes me feel valuable,” she said, “and gives me a sense of gratitude.”

Photos by Eric Younghans, USF Health Office of Communications

A foundation in knowledge and a positive mentor helped second-year medical student James A. Mauro publish his research as first author in the Feb. 25 issue of the journal Gene.

James Mauro presented his research at this year’s USF Health Research Day.

The research article, which is Mauro’s first first-author publication, provides a new understanding for how transcription factors (proteins that bind to a gene and flag it to be expressed) work. They allow cells to act in a certain way, and larger genes have more transcription factor binding sites and are, therefore, more sensitive to stimulation than smaller genes. The finding could aid in new disease treatments, including those for cancer, Mauro said.

“Increasing levels of pro-proliferative transcription factors would normally be thought to make a cancer worse, but according to our research, it may actually kill it,” he said.

Mauro’s faculty mentor, and the senior author on the study, is George Blanck, PhD, professor in the Department of Molecular Medicine in the USF Health Morsani College of Medicine.

“James’ project is solid bioinformatics and genomics work,” Dr. Blanck said. “He has the great combination of knowledge of science and knowledge of code writing. If he hadn’t been able to write the (computer) code to break down the data, the results would never have surfaced.”

Mauro, who has an undergraduate degree in biotechnology and a master’s degree in medical sciences, is also vice president of information technology for the Medical Student Council in the Morsani College of Medicine. The significance of being first author while in medical school is not lost on Mauro.

“I put a lot of hard work into it and it feels very worthwhile to finally see it published,” Mauro said. “It’s also a little scary, too. Typing my name into PubMed or Google now comes up with my paper, but I’m proud to see it there.”

The experience also shows the impact a positive mentoring relationship can have for medical students.

“Working with Dr. Blanck was absolutely great,” Mauro said. “From day one, he was a pleasure to work with and supported me 100 percent of the time. Even when things would go wrong, as they often do in research, he always helped me to stay on track. We would often discuss the results or what new direction to go towards and Dr. Blanck always made sure to give my ideas and opinions equal weight to his own, which was important since it allowed me to take my project in different directions and truly allowed me to make it my own. Most importantly, to do research, and actually enjoy it, you need to find more than just someone willing to take you on, you need a mentor, someone who you can learn from, and also someone who can learn from you.”

The article can be found in the journal Gene, Volume 536, Issue 2, 25 February 2014, Pages 398–406. (link to article)