Two novel CAR T-cell therapies designed to attack solid tumors are showing signs of antitumor activity and tolerability in early clinical trial findings, fueling optimism about expanding this emerging form of immunotherapy beyond hematologic malignancies.
Prasad S. Adusumilli, MD
Two novel chimeric antigen receptor (CAR) T-cell therapies designed to attack solid tumors are showing signs of antitumor activity and tolerability in early clinical trial findings, fueling optimism about expanding this emerging form of immunotherapy beyond hematologic malignancies.
One trial is testing a CAR aimed at mesothelin (MSLN), and the other is evaluating a CAR that targets HER2. In choosing those targets, investigators hope to surmount one of the challenges of designing CARs for solid tumors: identifying targetable cancer-associated antigens with high expression that are not found on normal tissue.
The 2 FDA-approved CAR therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta), are directed at CD19, a glycoprotein expressed on the surface of malignant B cells. Tisagenlecleucel is approved for patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia and adults with relapsed/refractory (r/r) large B-cell lymphomas; axi-cel is indicated for adults with r/r B-cell lymphomas.1,2
Data from the 2 phase I solid tumor CAR trials, presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, illustrates this modality’s potential in solid tumors, according to Stand Up To Cancer (SU2C), which is supporting the trials.
For the MSLN-targeting study, investigators designed a second-generation CAR using a CD28-costimulated MSLN CAR, ICasM28z (NCT02414269) (Table 1). MSLN is commonly expressed in solid tumors, including 85% to 90% of mesothelioma samples, according to the AACR presentation.3 The participants in the study included patients with malignant pleural mesothelioma, lung cancer, and breast cancers; 40% had received ≥3 lines of prior therapy.3
Findings show preliminary activity among 21 patients after a single dose of iCasM28z CAR, which was administered intrapleurally with or without cyclophosphamide preconditioning.3
Investigators reported CAR T-cell persistence in the peripheral blood of 13 patients during the 38-week evaluation period, a finding associated with a ≥50% decrease in the levels of MSLN-related peptide in blood and tumor regression on imaging. Objective responses occurred in 8 of 11 patients who received a combination of cyclophosphamide conditioning therapy, the CAR T cells, and at least 3 doses of an anti—PD-1 agent.3
Injecting the T cells directly into the pleural cavity proved to have no evidence of on-target, off-tumor, or therapy-related toxicity; there was no evidence of CAR T-cell related toxicity, such as neurotoxicity or cytokine release syndrome, greater than grade 2.3 “Solid tumors are notorious for not letting T cells enter inside the tumor and rendering them ineffective even following efficient infiltration by multiple immunosuppressive mechanisms,” Prasad S. Adusumilli, MD, lead investigator of the phase I trial, said in an interview with OncologyLive®.
“We discovered that CAR T cells, after successfully entering and lysing part of the solid tumor, were rendered ineffective by induced PD-1/PD-L1 pathway,” added Adusumilli, who is deputy chief of the thoracic service and head of solid tumors cell therapy at the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer in New York, New York.
The concept of applying an anti— PD-1 agent was tested in 14 patients in the phase I study after lack of toxicity was observed from the CAR T cells. After up to 21 cycles of therapy with an anti–PD-1 agent, no toxicity was reported, and 2 patients experienced complete response at 32 and 60 weeks. The combination therapy will be tested further in a trial set to begin recruitment in 2019.3
Aiming at HER2
In the HEROS study, investigators are testing a CAR with an antibody specific for HER2 that contains CD28 signaling in pediatric and adult patients with advanced HER2-positive sarcomas (NCT00902044) (Table 2). One of the more common types of sarcoma, osteosarcoma, is thought to be HER2 positive in up to 40% of patients; additionally, this subtype is associated with a higher likelihood of tumor metastasis.
In the study, participants receive up to 3 infusions of 1 X 108/m2 CAR T cells after lymphodepletion with fludarabine either alone or with cyclophosphamide.4 Findings from an interim analysis were reported at AACR for 10 patients with a median age of 14 years (range, 4-54) and different sarcoma types; 5 had osteosarcoma; 3, rhabdomyosarcoma; and 1 each, synovial sarcoma and Ewing sarcoma.4 Patients had received up to 5 prior therapies. One of the patients with rhabdomyosarcoma enrolled and relapsed, then was reenrolled later and re-treated.
Among these patients, 2 achieved a complete response and 4 had stable disease. Overall survival among the responders ranged from 4.5 months to 37.6 months, with 5 patients still alive at last follow-up.4
CAR T cells expanded in all but 2 patients and were detected by quantitative polymerase chain reaction in all 10 patients 6 weeks following infusion. Those who had initial responses to treatment were administered another 5 CAR T-cell infusions without lymphodepletion.
“Sixty percent of the enrolled patients achieved either tumor stabilization or complete response; 2 patients remain in remission at near 3 years of follow-up,” Meenakshi Hegde, MD, a pediatric oncologist at Texas Children’s Hospital in Houston who is investigating the therapy, said in an interview. “In these trials, encouraging antitumor activity in sarcoma was seen and safety of targeting HER2 was established.”
Barriers to Solid Tumors
Although identifying targets is the first hurdle investigators face in developing CARs that target solid tumors, delivering the therapy is another. The microenvironment is hostile to T cells and differs by the site of the metastases. “[This is] unlike hematologic malignancies that are distributed widely in sites where T cells can enter at higher numbers, such as bone marrow and lymph nodes,” Adusumilli said.
Despite the promising antitumor activity in both trials, much work remains for developing sustainable therapeutic options. “Achieving durable clinical responses in a larger cohort of patients with solid tumors requires a substantial amount of improvements to the current CAR T-cell approaches,” Hegde said. “Specifically, methods to improve the CAR molecule, CAR T-cell trafficking to tumor sites, and optimizing their function within the immune-inhibitory microenvironment are key to continued improvement.”
Developing options for patients who do not show meaningful response to other lines of therapy is an important focus for CAR investigators. “Akin to primary and secondary chemotherapy, targeted T cells would be well poised to eliminate tumor cells prior to and/or after tumor debulking,” Hedge added.
Although investigators intend to build on the progress in CAR T-cell therapy in solid tumors, they are proceeding with caution. “We have to set expectations for what we think is going to happen in the first couple of trials in solid tumors,” said Marcela V. Maus, MD, PhD, director of cellular immunotherapy at Massachusetts General Hospital in Boston, whose research is supported by SU2C. “Everybody likes to jump on the bandwagon when [a trial] is really successful, but I think it may take a couple more fits and starts with solid tumors.”
“We’re starting to see some responses like what Dr Adusumilli showed with local injection,” Maus added. “We’re seeing combination of CAR plus checkpoint blockades, multiple infusions, and I think we are going to see some real movement of the needle in just the next 5 years.”