Next-Generation CAR-T

Chimeric antigen receptor T-cells (CAR-Ts), reviewed last week, are a powerful new weapon for oncologists to use in their fight against cancer. These engineered T-cells are designed to home in on and kill malignant cells, and have proven highly effective at treating otherwise incurable leukemias and lymphomas. However, they are not without problems. The current generation of CAR-Ts have the potential to cause serious safety issues in some patients. While highly effective against blood cancers, their results have been less impressive when targeting solid tumors. Finally, existing CAR-T therapies are patient-specific, which adds to their expense and the time required for their production. In this WEEKLY, we’ll take a look at each of these issues in turn and examine some steps that are being taken to address them.

Eye Of The Storm

One of the reasons CAR-T treatments are so powerful is because once activated, they multiply inside of the body, and release inflammatory molecules called cytokines. Cytokines serve two core functions:

• They activate additional white cells to fight pathogens.
• They stimulate white blood cells to move toward inflammation.

Cytokine signaling makes for a quick, strong, and usually appropriate immune response via a positive feedback loop in which activated white cells release more activating cytokines. The response typically dissipates when the pathogenic cells have been destroyed. However, sometimes the feedback loop just keeps looping. This phenomenon is called a cytokine storm, and leads to acute inflammation with high fever, swelling, and/or nausea. It sometimes causes serious tissue damage and even death. For example, excess fluids can seep into the lungs and cause them to fail. Although uncommon, cytokine storms pose the biggest risk of CAR-T treatments.

Calming The Storm

Actemra (Roche; Basel, Switzerland) has been approved for the treatment of cytokine storms in patients undergoing CAR-T treatments. The drug is a monoclonal antibody therapy designed to “mop up” excess interleukin 6, an inflammatory cytokine.

Biopharma companies are also working on new CAR-T treatments with controls to regulate cytokines and minimize storms. First generation CAR-T therapies induce maximum white cell activity—a full cytokine barrage. Their intensity makes tamping down the cytokine response impossible.

In one example of next generation therapy, patients take an adjunct small molecule drug during their CAR-T infusion. This sidekick medicine provides an on/off switch for the CAR-T therapy. It turns on the therapy to fight the cancer. Should a cytokine storm ensue, doctors can immediately withdraw the adjunct drug, turning off CAR-T and ultimately stopping cytokine release. Bellicum Pharmaceuticals (Houston, Texas; Phase I/II clinical testing for pancreatic, gastric, and prostate cancer) and Obsidian Therapeutics (Cambridge, MA; Preclinical) are developing small molecule switches to control CAR-T activation.

Solid Tumors

So far, CAR-T has proven most effective against blood cancers. Targeting solid tumors is more difficult, in large part because tumors contain cells that secrete anti-inflammatory cytokines, or cytokines that turn the immune response down. Solid tumors can also be difficult to penetrate, meaning CAR-Ts can’t always effectively access malignant cells on the tumor’s interior.

One way to combat this immunosuppressive environment is to engineer CAR-Ts to secrete specific inflammatory cytokines designed to beef up their ability to attack solid tumors. Obsidian Therapeutics is developing turbo-charged CAR-Ts that produce interleukin 12, a cytokine known to combat the tumor’s immunosuppressive environment. When combined with Obsidian’s small molecule controls for safe activation of the CAR-T, this immune-activating protein should be released in a safe and controlled manner.

Natural Killers

Another approach to targeting solid tumors with CAR technology is to use a different type of white blood cell that more easily penetrates solid tumors. Enter natural killer (NK) cells. These white blood cells are a part of our innate immunity, or the immune response that is activated immediately in response to any threat. Most immunologists think that NK cells play a role in recognizing and killing off cancer cells that arise in our body, and are able to more easily penetrate solid tumors. Problem is, early-stage cancers often aren’t recognized as a threat. By modifying NK cells with a CAR that targets them to a specific tumor type, their killing ability can be put to work. CAR-NK therapies are now in Phase I/II clinical studies for B-cell malignancies led by oncologists at the University of Texas MD Anderson Cancer Center in Houston in partnership with Takeda (Tokyo, Japan).

Chowing Down On Cancer

Macrophages are our body’s scavengers. The name derives from a Greek phrase meaning “big eater.” These cells kill infectious or diseased cells by surrounding and digesting them. Think of a sloppy Pac-Man. After a macrophage meal, minute bits of foreign cell proteins or antigens remain on its surface. The leftovers help activate some of the immune system’s other defenses, such as killer T-cells.

Carisma Therapeutics (Philadelphia, PA) is carrying out preclinical development of CAR-macrophages to destroy specific cancer cells. The amped-up macrophages will simultaneously trigger other immune cells to recognize and attack those same antigen-bearing cells. Like other macrophages, CAR-macrophages can penetrate solid tumors much more effectively than basic T-cells.

Off-the-Shelf CAR-T

First generation CAR-T has been patient-specific, or autologous. In other words, T-cells are first removed from the patient to be treated, modified, and infused back in. Customizing CAR-T in this manner is time consuming and expensive but necessary to avoid immune rejection.

A few different companies are exploring ways to create allogeneic or “off the shelf” T-cell therapies that can be used with any patient. The trick is to remove the telltale signs that allow the recipient’s immune system to recognize the engineered T-cell as foreign. Strategies in preclinical development use genome editing to remove the genes responsible for immune rejection. Companies working on developing off-the-shelf CAR-T therapy for hematological malignancies include Cellectis (Paris, France; Phase I), Celyad (Mont-Saint-Guibert, Belgium; Phase I), Allogene (South San Francisco, CA), and Poseida (San Diego, CA; preclinical).

We’re still wowed by first-generation CAR-T, but biopharma companies have safer, more effective, and more versatile second-generation therapies coming down the pipeline. We’ll be watching their development closely.