How MSK Is Improving CAR T Cell Therapy for Cancer Treatment

Administering a dose of a treatment that will remain in a patient's body to help them continue fighting cancer may seem like an impossible mission. But is not. This type of immunotherapycalled CAR T cell therapyIt is one of the most interesting fields in cancer treatment today.

What are CAR T cells and how do they treat cancer?

Think of it as creating “cellular killers,” trained to eliminate cancer cells. T cells from the patient's own immune system are extracted and then equipped in the laboratory with special tools that recognize specific targets on the surface of a cancer cell. When these weaponized cells are returned to the patient, they patrol the bloodstream like elite soldiers on search-and-destroy missions attacking those targets, leaving minimal collateral damage and resuming action if the cancer cells return.

MSK CAR T cell discoveries and further research

For more than two decades, scientists at Memorial Sloan Kettering Cancer Center (MSK) have been pioneers in this field. Design and conduct of clinical trials using CAR T cell therapy.. They have invented up to 20 CAR T technologies so far. MSK's discoveries have made CAR T cell therapy especially effective in treating patients with blood cancers, including certain leukemias and lymphomasas well as multiple myeloma.

But there are currently major obstacles preventing CAR T-cell therapy from helping more patients:

• The cells can take weeks to prepare and are expensive because they are designed individually for each patient.

• Many people do not respond to treatment or the cancer returns after it works. It can also have serious short-term side effects.

• CAR T cells have not worked well against solid tumors, which make up the vast majority of cancers.

Every day at MSK, scientists and doctors work to overcome the obstacles to this treatment, whose full name is “chimeric antigen receptor T-cell therapy.” "Antigen" is a protein that exists in abundance in cancer cells but not in normal cells. CAR T cells are designed to selectively attack these antigens, destroying the cancer.

"By investigating how T cells are connected and what receptors make them work, our laboratories can continue to push the boundaries of this revolutionary treatment," he says. physician-scientist Michel Sadelain, MD, PhD, who first engineered T cells 30 years ago. As Director of the Cellular Engineering Center and through his laboratory at the Sloan Kettering InstituteDr. Sadelain has continued to lead the field.

His lab is one of more than a dozen at MSK focused on improving CAR T-cell therapy in the following ways:

Preventing T cell exhaustion: MSK helps them keep fighting

T cells can lose their potency over time (a phenomenon known as T cell exhaustion), but Dr. Sadelain's lab found a way to continue the fight by inserting a molecule called 1XX into the T cell genome at a precise location called TRAC. His team used the new CRISPR gene editing technology for this groundbreaking engineering feat.

The laboratory's advancement is now materializing in patients. In early 2023, MSK launched a clinical trial, led by hematologic oncologist Jae Park, MDto try these CAR T cells fortified against a type of lymphoma. The translation from the laboratory to the clinic was made possible by Isabelle Rivière, PhD, and the Cell Therapy and Cell Engineering Facility in MSK. "If the cells are more powerful and last longer, we would ultimately need fewer, which could make manufacturing easier and less expensive," says Dr. Park.

How MSK is overcoming CAR T cell resistance

Another major challenge for CAR T is that cancers develop resistance to the treatment by producing fewer target antigens. This problem, known as antigen escape, allows the cancer to come back with a vengeance. But Dr. Sadelain and his colleagues used CRISPR to increase the sensitivity of T cells to antigens by at least tenfold, allowing the CAR T cell killers to finish the job, even with fewer targets guiding their path. .

These redesigned cells are called HLA-independent T cell receptor T cells (HIT).

"This could really broaden the field," says Dr. Sadelain. "We may no longer be limited to targeting antigens that are abundant for CAR T cells to function."

Allow CAR T cells to penetrate solid tumors

One of the main reasons CAR T cell therapy has not worked in solid tumors is that it is often difficult for T cells to penetrate them. Like a moat around a fortress, tumors are also surrounded by cells and molecules that hinder T cells until they run out of steam.

But the laboratory physician-scientist Prasad Adusumilli, MDis trying to solve this problem for CAR T cells in multiple ways, including:

Another method to make CAR T cells work in solid tumors is to turn the cell into a "micropharmacy." A completely new type of CAR T cell has been designed by physician-scientist David Scheinberg, MD, PhD, President of the Experimental therapeutic centerIn collaboration with chemical biologist Derek Tan, PhD, President of the Chemical Biology Program.

These T cells can activate a toxic drug payload directly into a tumor, killing both tumor cells that contain the cancer marker and nearby cancer cells that do not. Fittingly, the name of these cells is SEAKER (Synthetic Enzyme Armed Killer).

“These cells combine the targeting power of immune cells with the ability to generate a potent anti-cancer drug right at the site of a tumor. “It's a double whammy against cancer,” says Dr. Scheinberg.

Looking inside cancer cells

Currently, CAR T therapies can only attack target proteins located on the outside of cancer cells, a feature that limits their effectiveness and safety, especially against solid tumors. MSK physician-scientist Christopher Klebanoff, MDfocuses on an innovative and next-level approach.

His team is investigating ways to genetically reprogram T white blood cells to recognize mutated cancer-causing proteins located inside cancer cells, using a technique called T cell receptor therapy. This approach engineers T cells to allow them to inspect the inside of cells in search of rogue proteins that are unique to tumors.

"We are using a genetic engineering approach to help boost T cells in a new way," says Dr. Klebanoff. "It's similar to giving immune cells X-ray vision."

Making CAR T-cell therapy easier for patients and more accessible

The need for CAR T cells to be tailored to each patient makes the treatment expensive and time-consuming. That's why researchers are striving to produce standardized CAR T cells. One “off-the-shelf” therapy would use cells taken from healthy donors, known as allogeneic transplant – which would then be genetically modified and stored in large batches, ready for treatment.

"CAR Ts may never be widely used if they have to be made one at a time, per patient," says Dr. Scheinberg. "We really want something that's waiting in a freezer: you order it, you thaw it, and you infuse it into the person the next morning."

Multiple Myeloma Specialist Sham Mailankody, MBBS, has reported encouraging results Using Donor CAR T Cells to Treat Multiple Myeloma in a small group of patients. These cells were modified using a virus.

Reducing the risk of graft-versus-host disease with donated CAR T cells

In the lab, a more precise engineering technique could prevent the downside of using donor CAR T cells: a serious side effect called Graft versus host disease, which occurs when the donor's cells attack the patient's normal cells. Using CRISPR technology, MSK researchers are studying how to modify CAR T cells to disable the part that triggers this side effect.

In turn, to prevent a patient's immune cells from attacking the donor's CAR T cells, Dr. Scheinberg's lab has developed new cells that could defend against this attack, using what he calls a "protective CAR T cell." ".

"These CAR Ts are designed specifically to be available on the market because that's where rejection is such a big issue," says Dr. Scheinberg.

Without a doubt, making CAR T-cell therapy a truly transformative cancer treatment requires the continued drive and ingenuity of MSK scientists. But the pace of discovery is accelerating thanks to new technologies like CRISPR. Scientists who previously only imagined changing a cell's genes can now do so. With exquisite precision, they can arm immune cells to continually attack cancer. It is a mission that is now possible.