Creating Monsters to Fight Cancer

Creating Monsters to Fight Cancer

Creating Monsters to Fight Cancer

TGen partners with City of Hope to re-energize the body's own immune system against cancers

In Greek mythology, a Chimera is a hybrid creature composed of more than one animal, specifically a fire-breathing monster with the head of a lion, the body of a goat and a tail like a serpent. In developing new treatments that harness a patient’s own immune system to fight cancer, Chimeric Antigen Receptor T cells, or CAR T cells, are among the promising new immunotherapies being developed by TGen and City of Hope. For tumors, CAR T cells might as well be fire-breathing monsters.

How it Works

Clinicians remove immune system T cells from the bloodstream of an individual cancer patient and re-engineer them in the laboratory using a hybrid of proteins. This process creates the CAR T cells. Treatment consists of reintroducing the CAR T cells into the patient’s bloodstream, whereby they hunt down and destroy the targeted cancer.

CAR T cells, once they are injected back into the patient, propagate and persist, which is why CAR T therapy can provide both a rapid and long-term response, and the possibility of complete remission. At least, that’s the way they have worked successfully in blood cancers, such as Leukemia.

Now, TGen and City of Hope researches are teaming up to see if they can get CAR T cells to work on solid tumors, including breast, pancreas and brain cancers.

More Ways to Harness Immune System

City of Hope and TGen investigators recently opened two clinical trials at City of Hope’s Duarte, California, campus to test the effectiveness of combination immunotherapies to fight advanced liver, stomach, and esophageal cancers.

Both trails use an experimental immune system activation agent, IRX-2, produced by Brooklyn ImmunoTherapeutics. The trials combine IRX-2 with nivolumab for liver cancer patients, and IRX-2 with pembrolizumab for stomach and esophageal cancer patients. Both nivolumab and pembrolizumab are among a relatively new class of FDA-approved immunotherapies known as immune checkpoint antibodies.

“We’re trying to turn potentially ‘cold tumors’ – those with strong fortresses nearly impenetrable to the immune system – into ‘hot tumors’ that have walls equipped with ladders for immune T cells so that more patients can derive benefit from treatment with immunotherapy,” said Dr. Daneng Li, a co-principal investigator on the studies and an Assistant Clinical Professor in the Department of Medical Oncology and Therapeutics Research at City of Hope.

Dr. Sunil Sharma, Director of TGen’s Applied Cancer Research and Drug Discovery Division, is also a co-principal investigator on the clinical trials. Dr. Sharma is supervising DNA, RNA and protein sequencing of tumor tissue to potentially identify biomarkers that can better target the treatments.

“After successful laboratory testing, we are excited to offer this new therapeutic approach for our patients,” Sharma said. “We hope this unique immunologic approach will storm the walls surrounding these cancers and defeat these malignancies.”

City of Hope Cancer Transplants

City of Hope has one of the nation’s most celebrated bone-marrow transplant programs to fight blood cancers like leukemia and lymphoma. And while bone-marrow transplants themselves are not immunotherapies, the body’s immune system plays a critical role in the success, or failure, of these treatments.

Dr. John Altin, an Assistant Professor in TGen’s Pathogen and Microbiome Division, is working with City of Hope bone-marrow transplant expert, Dr. Ryo Nakamura, to fend off an often fatal post-transplant syndrome known as Graft Vs. Host Disease (GVHD), in which the life-saving bone marrow transplanted from a healthy person goes rogue and sees the patient’s body as an enemy to be attacked.

“One of the big problems in bone marrow transplantation is GVHD. We are developing an atlas of alloimmunity,” explains Dr. Altin, “trying to predict who may develop this serious outcome.”

It is not always possible to find a perfect donor match. There may be many potential donors available for a given patient.

“What we’re aiming to do is develop an algorithm that helps select which donor is the best match; which has the least risk of an adverse outcome,” said Dr. Altin, whose atlas will map all the possible compatibilities between donors and recipients. Adding detailed information from each new case to the atlas helps refine future compatibility match-ups.

Vaccine for blood cancer

Dr. Altin also is working with City of Hope’s Dr. Larry Kwak on the development of a vaccine for B-cell lymphoma. Like a snowflake, the genetic make-up of each lymphoma tumor is unique. Researchers use this unique idiotype as the basis of a vaccine made specifically for each patient.

“We’ve started working together on taking blood samples of those vaccinated, and testing to see if the vaccine has generated an effective immune response against the cancer,” Dr. Altin said. “It has the potential to be very powerful, because it’s targeted towards each individual’s particular tumor.”

TIL: Tumor Infiltrating Lymphocytes

Cancers often find ways to hide themselves from the body’s immune system.

But sometimes, immune T cells find a way to burrow into the cancer before the cancer can seal itself off. Once inside the cancer, these immune system cells become exhausted, dysfunctional, having allowed the tumor in some way to turn them off.

“T cells represent the immune system’s initial attempt to respond to the tumor,” explains Dr. Altin, who is working with Dr. Sharma at Scottsdale’s HonorHealth on this new way of re-training the immune system’s T cells. “They live inside the tumor. We’re trying to harness these cells as a way of treating cancer.”

First, doctors remove the Tumor Infiltrating Lymphocytes (TIL) cells from inside the patient’s tumor. Then — similar to CAR T cells — the TIL cells are manipulated in the lab. Unlike CAR T cells, the TIL cells are incubated in the lab with specific peptides from the cancer.

“We are trying to re-energize them,” Dr. Sharma said. “In the lab, we try to skew the errant T cells’ repertoire, so they can again recognize the tumor and attack it.”

With both TIL and CAR T cells, they are altered in the lab with the intent of re-igniting the power of the patient’s own immune system.

The process for developing TIL cells, however, differs from CAR T cells in a significant way. CAR T cells start as T cells taken from the patient’s bloodstream, while TIL cells come specifically from inside the patient’s tumor, Dr. Altin said. “The TIL cells often already come with some sort of specificity, or targeting, against the tumor.”