CAR T-cell therapy burst onto the scene as a revolutionary treatment for cancer patients in 2015, when it was introduced in clinical trials primarily for patients with lymphoma and leukemia. Since then, it has transformed the course of disease, primarily for blood cancer patients, with many clinical trials now exploring the approach for solid tumor patients. Through this highly tailored form of immune effector cell (IEC) therapy, typically a patient's own immune cells — known as T cells — are genetically re-engineered to identify and kill cancer cells.
Eric Smith, MD, PhD
"I like to think of T cells as the army, and what makes them so special is that they will make genetically identical copies of themselves when they see the enemy. It's a self-perpetuating army that we’ve educated to attack cancer," says Eric Smith, MD, PhD, director of translational research, Immune Effector Cell Therapies, at Dana-Farber.
This army is mobilizing in new and exciting ways. CAR T-cell therapy is being evaluated as a first-line treatment before chemotherapy for certain blood cancer patients. The time required to extract a patient's T cells and reengineer them is shrinking. And Dana-Farber physician-scientists are even using the therapy on a notoriously formidable enemy: solid gastrointestinal tumors.
Accelerating the Fight Against Blood Cancers
Chemotherapy is often effective for a large portion of blood cancer patients, who traditionally receive it as a first line of treatment. However, some patients continue to relapse. For this subset, CAR T-cell therapy is a valuable alternative. Dana-Farber Brigham Cancer Center was one of the first centers to make the 6 FDA-approved CAR T-cell therapies available as standard of care to these patients.
Therapy has led to "deep response rates, and more importantly, responses that are durable — meaning that they go on for years in anywhere between 40 and 50% of patients," says Caron Jacobson, MD, MMSc, medical director of the Immune Effector Cell Therapy Program at Dana-Farber. "We're offering a potentially curative therapy to patients who really didn't have other treatment options and are absolutely extending survival for patients with these diseases."
Caron Jacobson, MD, MMSc, is exploring several new ways that CAR T-cell therapy might be deployed, such as its potential use as a first-line treatment for lymphoma.
On the heels of that success, there have been initiatives to try to move these CAR T cells into earlier lines of therapy: Jacobson points to studies in patients with diffuse large B-cell lymphoma, the most commonly diagnosed form of lymphoma, which showed impressive response rates to CARs.
Patients typically would have received multiple lines of previous treatment and relapsed through those lines — and had minimal other FDA-approved options — before being referred for CAR T-cell treatment. This is changing.
"One of the things I'm most interested in is: Are there patients who probably shouldn't be getting chemotherapy as a first-line treatment?" Jacobson says.
"Now, there are newer trials trying to move up effective cell therapies earlier in the disease course. We've started clinical trials for patients who have a real unmet medical need," Smith says.
Dana-Farber is participating in the ZUMA-23 study, which is enrolling high-risk large B-cell lymphoma patients to further determine whether using CAR T-cell therapy as a first-line treatment is preferable to the standard six rounds of chemotherapy.
"This could be a potentially game-changing treatment for a high-risk subset of patients," Jacobson says.
Dana-Farber is also exploring how to deploy CAR T-cell therapy in new scenarios, such as lymphomas that affect the central nervous system. In one investigator-initiated study, 67% of patients experienced a complete response, lasting 11 or more months in half of these patients.
As follow-up continues, she hopes that results support a larger, potentially multi-center study that could expand commercial indications of these cells into central nervous system lymphomas. She's also working with researchers at Dana-Farber Boston Children's Cancer and Blood Disorders Center to study the biologic underpinnings of the neurologic toxicity caused by CAR T cells. Indeed, despite its promise, CAR T-cell therapy can destabilize the nervous system: Common side effects include headache, confusion, and hallucinations, though these problems generally subside in a few days and can be managed while in the hospital.
"What makes me so excited to come to work every day is the fact that we're making real, palpable progress," Jacobson says. "To see CAR T-cell therapy move up a line of therapy is a piece of progress I haven't seen before in my career."
Smith, meanwhile, is especially optimistic about treatment for multiple myeloma, once a disease with a dismal prognosis. Now, patients who have relapsed or not responded to other treatments are living longer with treatments such as CAR T-cell therapy, although the disease currently remains incurable.
"For someone who's diagnosed with myeloma today, I'm optimistic that, if we continue to make progress in this and other technologies, they very well may be cured in their lifetime," Smith says. In the meantime, the future looks brighter for these patients.
"We see that, despite even having a high tumor burden, CAR T-cells expand and rapidly eliminate massive amounts of tumor within the first weeks. Patients are having good responses, they're having frequent deep remissions, and they're getting great quality of life from these therapies. The therapies that we have today are really transformative," Smith says.
Deploying CAR T-Cell Therapy to Treat Colorectal Cancer
One of the most exciting advances in CAR T-cell therapy involves solid GI tumors, which have been notoriously difficult to treat with IEC therapy. Imagine training a dart on a bullseye, with the bullseye being a specific protein outside a tumor cell. In solid tumors, the bullseye is too subtle. It would be like firing an arrow at a speck of sand.
Benjamin Schlechter, MD
"These cancers have so much in common with the underlying normal tissue that the immune system just simply can't tell the difference," says Benjamin Schlechter, MD, an oncologist in the Gastrointestinal Cancer Treatment Center at Dana-Farber.
However, the target is quickly coming into sharper focus, with no time to waste. Colorectal cancer is on track to become the leading cause of cancer death in adults under age 50 by 2030. Dana-Farber is the leading enroller on a phase 1 trial of a one-time cell therapy known as GCC19CAR-T, which specifically targets colon cancer by binding to GCC (guanyl cyclase C), a protein typically present in 70 to 80% of patients with colorectal cancer.
Here, CAR T-cells are engineered to target both GCC but also CD19 on B cells circulating in the bloodstream. This pairing causes the GCC T-cells to naturally activate, proliferate, and flow into the tumor, binding to and killing cancer cells with less disruption to healthy tissue than if the GCC cells were dispatched en masse. Because CAR T-cell therapy has been highly effective in lymphoma and myeloma once a high-quality target was identified, Schlechter hopes the same will be true for GI cancers.
"When the cells are infused into your body, they quickly grow inside of your blood, feeding off of those CD19-positive B-cells, and they rapidly expand, leading to a more natural expansion of these T-cells rather than giving you a huge, engineered dose," Schlechter says.
Still, patients may experience some intense side effects over 10 days or so, such as high fevers or diarrhea, which are generally treated on an inpatient basis with anti-inflammatory drugs and IV fluids.
The trial is enrolling patients now, and the process is straightforward. T cells from GCC-positive patients are collected intravenously, through a process known as leukapheresis. These cells are sent to a lab for genetic engineering over one to two months. Patients may receive chemotherapy as a bridge in the meantime. Before infusion, they receive lymphodepleting chemotherapy to suppress their existing immune system and facilitate expansion of their engineered CAR T cells.
Schlechter emphasizes that chemotherapy remains an important tool in the fight against cancer.
"Chemotherapy is highly effective. But chemotherapy must be done over and over again, and it injures both cancerous and normal tissue," he says.
CAR T-cell therapy, on the other hand, "is a fundamental redesign of your own immune cells to fight your cancer for you. I'm optimistic that we can find ways to safely deliver these treatments. I think it's very exciting."
Accelerating CAR T-Cell Delivery
The physical delivery of these cell therapies at Dana-Farber is possible largely thanks to the Connell and O'Reilly Families Cell Manipulation Core Facility (CMCF).
The CMCF works closely with academic and industry investigators to bring their experimental cell therapies into the clinic. They also manage experimental and FDA-approved cell therapies manufactured outside of Dana-Farber, as well as therapies manufactured on-site. On-site manufacturing is a cost-effective, time-saving development for patients.
Sarah Nikiforow, MD, PhD
"There's an overall shortening of time for the patient to receive their cell therapy in many instances with on-site production. We're also able to offer feedback to the clinical team in terms of how manufacturing is going and to adapt or optimize the patient's care plan. We're able to be nimbler if the product is manufactured here," says Sarah Nikiforow, MD, PhD, medical director at CMCF. Sometimes, manufacturing takes just 48 hours, with delivery to a patient within two weeks of initial immune cell collection.
Nikiforow is especially excited about bringing different types of cell therapy to even more solid tumor patients.
"What I envision over the next 1-2 years are huge steps forward in both efficacy and safety across multiple diseases [with CAR T-cell therapy]," Nikiforow says. "I'm seeing nuancing of how directed and how safe we can get the activity of these cells. My hope is not just that we will benefit future generations of patients with cancer. The field is moving so fast that even people diagnosed now will have increasing access to these types of therapies."
