乌鸦传媒

Chimeric antigen receptor (CAR) T-cell therapy has had a transformational impact on the treatment of aggressive hematologic malignancies. The therapies have given life-extending options to patients who have exhausted other potential options.

An obvious next step in the development and growth of CAR T-cell therapies has been the jump to solid tumors. Because of inherent differences between hematologic and solid malignancies, researchers expected solid tumors to pose more challenges.

The first approved CAR T-cell therapies were for B-cell non-Hodgkin lymphoma and leukemia. All of the therapies target CD19, an antigen that is ubiquitously expressed by B cells. Newer approved agents target B-cell maturation antigen (BCMA), also highly expressed on B cells. Subsequently, CAR T-cell therapies for multiple myeloma received FDA approval. Currently available agents target CD38, uniformly expressed by myeloma cells. Engineering CAR T cells to target solid tumors is not so straightforward.

CAR T-cell therapies for hematologic malignancies have targets that are found primarily in blood, lymph nodes, and bone marrow, which are relatively accessible to immune cells.

"When we think about solid tumors, they are primarily in epithelial locations, where immune cells cannot traffic as easily," said Lawrence Fong, MD, of the Fred Hutch Cancer Center in Seattle. "There are impediments to getting the immune cells to where the tumors cells are and killing them. By virtue of surviving the immune system and the immune response within a patient, solid tumors have figured out ways to repel immune cells."

CD19 and BCMA are expressed on normal cells as well as malignant cells, so the CAR T-cell therapies eliminate some healthy cells. However, patients can survive without B cells. With solid tumors, finding an antigen expressed on tumor cells but not healthy cells has proven to be a challenge.

"If you have an antigen and it targets the tumor cells but also targets the lung or other tissues in our body, that leads to toxicities that prevent us from seeing a benefit," said Fong. "It's what we call the therapeutic window. We need to be able to kill the cancer cells but not the normal cells. Sometimes that window is so narrow that we don't have enough of a therapeutic effect before we get toxicity."

Tumor-cell heterogeneity has represented a major obstacle to the development of CAR T-cell therapy for solid tumors, said Donald O'Rourke, MD, of Penn Medicine in Philadelphia, who has been evaluating CAR T-cell therapy for brain cancer.

"The cells on these tumors are much more heterogeneous than lymphomas or leukemias," he told 乌鸦传媒. "For example, CAR-T 19 targets CD19 on every B cell, but the EGF receptor mutations that we're targeting in glioblastoma are not on every glioblastoma cell. There is a regional distribution of the mutations, coupled with other mutations that create a heterogeneous target."

Additionally, tumor cells exist in a hostile, immunosuppressive microenvironment that "can shut down any kind of anti-tumor response in the brain."

"Persistence of the response, the length or durability of the response, is limited by the immunosuppression within the microenvironment," said O'Rourke. "That's really the major problem we're dealing with. We're doing pretty well with the heterogeneity, because we're seeing targeted elimination [of cancer cells] in our patients. We're having problems with persistence of cells, and we think it's that suppressive microenvironment that we have to deal with."

Despite the ongoing challenges, signs of progress are obvious. Fong pointed to the recent FDA approval of afamitresgene autoleucel (Tecelra), a cellular therapy for synovial sarcoma.

"It's a relatively infrequent cancer and the treatment is relevant only for patients with a specific HLA allele, which reduces the number of patients the treatment will work for," said Fong. "Nevertheless, this represents a huge advance, having an FDA-approved engineered cell therapy for a solid tumor."

FDA approval of tarlatamab (Imdelltra) for small-cell lung cancer offers another example of progress. The novel bispecific T-cell engager (BiTE) binds DLL3 on cancer cells and CD3 on T cells. Though technically not a CAR T-cell therapy, the agent "is not unlike CAR T-cell therapy in that we're redirecting T cells to target other antigens, DLL3 in this case, for a difficult-to-treat disease that represents a huge unmet need," Fong noted.

Another BiTE in development by Amgen on prostate cancer cells. In a , the treatment achieved a 40% response rate in heavily pretreated metastatic castration-resistant prostate cancer treated with the highest dose.

"That drug is actually entering phase III clinical trials that we're participating in," said Fong. "We're hoping that will become another T-cell engager that crosses the finish line in terms of targeting an even more common disease."

With validation of STEAP1 as a target, investigators want to know whether CAR T cells might be developed to target the antigen, he added.

O'Rourke and colleagues have been evaluating a bivalent , a frequently treatment-resistant disease that has a survival of about 6 months. The therapy simultaneously targets EGFR and interleukin-13 receptor alpha 2. In three clinical studies conducted over the past 10 years, the treatment has produced results that have sparked conversations about potential FDA approval.

Investigators have changed two aspects of the traditional CAR T-cell technique. Targeting two receptors increases the mutation coverage and addresses the issue of heterogeneity. Second, they switched from intravenous to intrathecal delivery.

"In the current trial we have treated 13 patients and we have five more to treat before we move on to the next trial," said O'Rourke. "We'll be moving the therapy up earlier in the course of the disease in the next trial because we think it will be even more effective. Even in the current study, we're seeing a number of patients with durable responses as outpatients, living 9, 10, 11 months, even over a year, with recurrent glioblastoma."

"We're seeing patients enter pretty interesting territory in terms of survival because you begin to get interested when you see anyone living over 6 months," he added.

FDA approval within 3 to 5 years is not outside the realm of possibility, he noted, "depending on whether we can accelerate the trial program."

Addressing the broader issue of applicability, O'Rourke said CAR T-cell therapy, in theory, has therapeutic potential for any type of tumor that has a promising target.

"We think the work we're doing now does have general applicability to other solid tumors," he said. "People will be able to use some of these strategies in lung cancer, melanoma, breast cancer. The EGF receptor that is our main target is commonly expressed in many tumor types. A tangential part of our program is to develop a CAR-T for brain malignancies that are not glioblastoma. They're metastatic from other sites, melanoma is a top priority because it does share targets with glioblastoma."

Researchers in the field have a keen interest in combination strategies, such as CAR T-cell therapy plus immune checkpoint inhibition. In patients with glioblastoma treated with the bivalent CAR T-cell therapy also received pembrolizumab (Keytruda), which did not improve results.

"I think that eventually the magic bullet will be a combinatorial strategy," said O'Rourke. "I think CAR-T will find a place in the patient journey, but it will need to be combined with other strategies in solid tumors because of the challenges of heterogeneity and immunosuppression."

Without mentioning a specific timeframe, Fong predicted more FDA approvals for CAR T-cell therapies for solid tumors.

"We know these approaches work," he said. "There is a whole host of activity around the world related to developing CAR T cells. This is an exciting time in the field. People are going in so many different directions that the collective knowledge is growing at an accelerated pace. This is really a great time to work in this field."

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