“Your cancer has spread” is terrifying news to hear. But it’s unfortunately common for people with colorectal cancer. The cancer is the third most common tumor globally and accounted for 930,000 deaths in 2020. One estimate suggests the disease could take up to 1.6 million lives in 2040.
Patients often die after colorectal cancer spreads to the liver, which makes removal extremely difficult. After the cancer metastasizes, treatment options are limited. Multiple rounds of full-body chemotherapy are the norm, but the therapy has severe side effects.
Patients have a survival rate of about 30 percent after five years, wrote Monica Casucci at IRCCS San Raffaele Scientific Institute and colleagues in a new paper.
The team’s research describes a more efficient, less toxic approach: CAR T therapy. Here, a patient’s own immune cells are extracted and fitted with proteins that enhance their ability to search and destroy cancers. The FDA first approved the revolutionary therapy in 2017 for people with a type of leukemia. Since then, six treatments have been approved for other blood cancers.
Casucci and her team have long sought to tackle metastasized colorectal cancer with CAR T. Compared to cancerous blood cells that naturally circulate in the bloodstream, solid tumors—for example, those in the colon, liver, or brain—are much harder to reach. The engineered cells must be directly infused into tumors with invasive surgery, an approach that’s even harder after a cancer has spread.
The new study aimed to treat solid tumors like blood cancer—with a single injection into a patient’s vein. The team engineered CAR T cells that could hunt down metastasized cancer cells. When infused into the veins of mice they found the engineered cells rapidly shrank tumors in the liver and large intestines without causing dangerous immune side effects.
The results “pave the way for a…clinical trial,” wrote the team.
Out-and-In
Our immune system already surveils cancer cells and sends T cells to destroy them before they expand. But cancers are tricky and rapidly mutate to evade the body’s immune defenses.
CAR T therapy uses genetic engineering to give natural T cells a boost.
Here’s how it usually works. Physicians first isolate T cells from a blood draw. They then insert genes encoding an extra “hook” protein that sits on the surface of the cells. This protein hook helps the cells locate and latch onto targeted cancer cells. Once infused back into the body, these superpowered cells are better at grabbing onto and destroying the cancer.
Success relies heavily on the hook’s design. These synthetic proteins—called CAR for chimeric antigen receptor—are designed to grab onto a specific cancer cell while ignoring healthy ones.
The first step is to find a protein target that’s unique to a type of cancer. Like all cells, the surface of cancer are dotted with proteins. These proteins form a sort of fingerprint.
Most blood cancers have similar fingerprints. But solid tumors are mashups of multiple cell types, each with its own signature, making it difficult to engineer targeted immune cells. These tumors can have attributes similar to healthy cells, wrote the team, meaning engineered T cells could inadvertently attack and cripple normal organs. Possible side effects also include cytokine release syndrome, where the immune system pumps out dangerously high levels of inflammatory molecules. In rare cases, the condition can be fatal.
Designer Missile
The team got to work with one goal in mind: Find a protein target that’s efficient and safe. After screening the genetic profiles of metastasized colorectal tumors from patients and scouring multiple protein databases, they landed on a protein called CDH17. Several gastrointestinal cancers—including colorectal cancers—express more of the protein than healthy surrounding tissues. Next, the team designed six versions of CAR T with protein hooks tailored to CDH17.
You can imagine these hooks as wobbly Lego structures with multiple sections. Some sections tunnel through the membrane of the immune cell. Others, on the outside of the cell, include the “hook” and a “hinge” that allows the protein to stretch, move, and flex so it can better detect and grab onto cancer cells. Yet another component anchors the protein to its host cell and, once a cancer cell has been found, sends signals inside that trigger its own cell to attack.
Two of their CAR T versions outperformed in tests. The team injected both either into the bloodstream or directly into the livers of mice with cancer that had metastasized.
The cells thrived and were roughly equally matched at fighting off cancer cells over a few weeks. Direct injection into the liver cleared out tumor cells faster, but the treatment was far more toxic compared to injection into the bloodstream. The mice experienced “irreversible weight loss,” wrote the authors, and all eventually died.
“Because rapid weight loss and fatal events have been recognized as clinical signs of CRS [cytokine release syndrome], we reasoned the toxicity observed might be” because of an overhyped immune response, wrote the team.
They were right. There was a spike in multiple inflammatory molecules when the CAR T cells were injected into the liver compared to a vein. The latter jab didn’t comprise the treatment’s efficacy and lowered the chances of a dangerous immune reaction.
Mice to Men
Both of the team’s leading CAR T therapies also worked in human tissues. In one test, the team transformed T cells from patients with advanced colorectal cancer that had spread to the liver into CAR T cells. They then made 3D mini-cancers, or cancer organoids, from the patients’ liver tumors. Both therapies grew in petri dishes and reduced the size of the organoids.
The CAR T cells ignored healthy intestinal cells, even when some also had a sprinkling of CDH17 on their surfaces. This is partly because the protein is nestled down into areas where healthy cells connect to each other, making it hard for CAR T to grab onto. In contrast, the protein is out in the open on the surface of colorectal cancer cells making them easier targets.
Although the study was only in mice and lasted a few weeks, it adds momentum to CAR T therapy for solid tumors. Another treatment for throat and stomach cancer is already in a phase 2 trial with promising initial results: The first phase increased survival rates compared to existing medications, although only for a few months. Many other similar trials are in the works.