New CAR-T Cell Therapy, Given with Keytruda, Is Safe and Effective in Treating Diffuse Large B Cell Lymphoma

October 13, 2020

Combining the immunotherapy Keytruda with a CAR-T cell therapy that targets the proteins CD19 and CD22 generates complete responses with minimal side effects, results from an early study demonstrate.

Adding a new type of CAR-T cell therapy to the immunotherapy Keytruda (pembrolizumab) in patients with recurrent or drug-resistant diffuse large B cell lymphoma (DLBCL) may induce complete remissions without causing some of the key severe side effects that might be expected with this kind of regimen.

The results came from a phase 1 study of AUTO3, the first CAR-T cell therapy to target both CD19 and CD22, proteins that help fuel DLBCL, an aggressive form of non-Hodgkin lymphoma that affects B lymphocytes. CAR-T cell therapy involves the collection of a patient’s cancer-fighting T cells, which are then engineered in a lab to better recognize and attack the disease and finally reinfused into the patient. Keytruda is an immunotherapy known as a checkpoint inhibitor, which works by inhibiting the activity of a protein that would otherwise restrict the aggressiveness of the immune system.

In the Alexander study, researchers found that two side effects that can arise with the administration of immunotherapy — a health issue known as cytokine release syndrome, which occurs when the immune system attacks healthy organs, and neurotoxicity, meaning damage to the central nervous system — rarely occurred at severe levels with the AUTO3 plus Keytruda regimen.

The findings were reported by lead study author Dr. Eleni Tholouli of Manchester Royal Infirmary in Manchester, U.K., during the European Society for Medical Oncology Virtual 2020 Congress.

Tholouli and her team embarked on the study because, while approved CD19-directed CAR-T cells are effective in patients with this condition, relapses are common among those who receive them.

The study tested three dose levels of the CAR-T therapy — 50 million, 150 million and 450 million cells — with patients escalating to the next highest dose after tolerating the previous one. Patients were divided into three groups to receive AUTO3 alone; with three doses of Keytruda given three weeks apart starting on day 14; or with a single dose of Keytruda given on day one of treatment. In advance of the administration of Keytruda and in combination with it, patients received the lymphodepleting chemotherapies fludarabine and cyclophosphamide.

The study’s primary goal was to measure the frequency of dose-limiting side effects, as well as side effects that were serious, severe or deadly. Secondary goals included measuring the overall response rate, which included all partial and complete responses; the complete response rate; and biomarkers, such as gene mutations, associated with response or resistance to the regimen.

Treated in the study were 35 patients whose median age was 59, most of them male and with stage 4 disease, who had received a median of three prior therapies. Of those patients, 54% had disease that was treatment-resistant or recurrent, 77% had disease classified as DLBCL not otherwise specified, and 23% had transformed DLBCL, meaning that the disease started as a less aggressive lymphoma and turned into DLBCL.

Escalation from the lowest to the highest dose of CAR-T therapy, given in combination with one-time or repeated Keytruda, was completed without side effects that required doses to be lowered, the researchers reported.

Treatment-related side effects that were serious and occurred in 25% or more of the study patients were neutropenia (87%), thrombocytopenia (57%) and anemia (48%), all blood count problems. Most serious side effects were blood-related and reversible.

There were no cases of severe cytokine release syndrome or neurotoxicity of any grade at the 50 million dose. Across all patients and dose levels, 23% of the study population experienced mild cytokine release syndrome and 11% experienced moderate cytokine release syndrome, Tholouli reported. She said that five patients received the anti-inflammatory drug Actemra (tocilizumab) to treat that side effect.

“Based on our experience, this profile appears clearly superior to that of currently approved CD19 CAR-T products,” she said.

Regarding neurotoxicity, she said that three cases were reported, two of them rated as severe. Tholouli noted that those cases were considered atypical and were associated with disease progression, narcotic use, sepsis and other factors; patients who responded to the drug regimen did not experience neurotoxicity. That result supports the finding that the drug regimen is safer than currently approved CAR-T treatments, Tholouli said.

Among the 22 patients treated at the 150 million dose with either regimen of Keytruda, the overall response rate was 68% and the complete response rate was 54%. Among the 14 patients who received the 150 million-cell dose of AUTO3 and the day-one Keytruda, the overall response rate was 71% and the complete response rate was 64%. One or more complete responses were seen at every dose level, Tholouli said.

She added that, of 15 patients who achieved complete responses, 93%, or 14, retained that status six months later without any progressive disease. The one patient who experienced progressive disease after a complete response was treated at the 50 million dose and did not receive Keytruda, she noted.

Researchers selected the 150 million-cell regimen with day-one Keytruda as the dose to test in a phase 2 trial that is now enrolling patients on an outpatient basis in the U.K. and U.S.

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