Experimental IL-15 cancer drug revives exhausted T cells in early tests
Scripps researchers say SAR’877 targets immune stimulation to worn-down T cells, with animal data and early patient testing supporting further study.
By Priya Raghavan · Science Reporter
3 min read
An experimental cancer immunotherapy from Scripps Research revived exhausted immune cells in laboratory and animal studies without broadly inflaming the immune system, according to findings published in JCI Insight. The work matters because existing immunotherapies can fail, lose effect over time or cause serious immune-related side effects.
The drug, called SAR’877, is being evaluated in an ongoing phase 1/2 clinical trial, according to Scripps Research. The institute said early patient testing has shown signs of activity, including in people whose cancers had stopped responding to other immunotherapies.
John Teijaro, a Scripps Research professor and co-senior author of the study, said the results show an immune-stimulating signal can be delivered to the cells most in need of it. He said the approach restored function more effectively than other methods his team had tested in that setting.
How the drug is designed to work
SAR’877 is a bispecific molecule, meaning it combines two immune-related functions in one treatment. According to Scripps Research, one part targets PD-1, a molecular brake on T cells that checkpoint inhibitor drugs such as pembrolizumab are designed to block.
The other part is a weakened form of interleukin-15, or IL-15, a cytokine that can boost immune cell activity. Scripps researchers said the IL-15 component was engineered to act mainly on nearby cells, reducing the broad immune activation that has limited earlier cytokine-based approaches.
The treatment is aimed at T cell exhaustion, a state in which immune cells lose potency after prolonged exposure to a threat such as a tumor or chronic infection. Scripps Research said exhaustion can help prevent tissue damage from an overactive immune system, but in cancer it can give tumors room to keep growing.
Mouse studies showed targeted immune activation
Teijaro’s team tested a mouse-adapted version of SAR’877 in a chronic viral infection model developed earlier in the laboratory of Scripps Research professor Michael Oldstone. The institute described that model as a long-used tool for studying whether therapies can restore weakened immune responses.
In those experiments, Scripps researchers said the drug cleared virus from blood and kidneys more effectively than a PD-1-blocking antibody alone, IL-15 alone or the two given together as separate treatments. Immune-cell analyses showed SAR’877 activated selected T cell groups already prepared to respond to the virus, rather than stimulating immune cells broadly, according to the study.
The team also reported an unexpected role for CD4+ helper T cells, which support other immune cells. Cancer immunotherapy research often focuses on CD8+ killer T cells, but Scripps said the helper-cell response was central in these experiments.
Teijaro said the researchers did not expect IL-15 to have such a strong effect on CD4+ cells. When the team removed those cells from mice, much of the drug’s benefit disappeared, according to Scripps Research.
Tumor models and next questions
The researchers also tested SAR’877 in 12 mouse tumor models, according to Scripps Research. The institute said the drug reduced tumor size in all 12 models and eliminated tumors in some mice, including more than two-thirds of mice with liver cancer and breast cancer models.
The JCI Insight paper was authored by Isaraphorn Pratumchai and colleagues under the title “PD-1–targeted IL-15 mutein activates CD8+ and CD4+ T cells in infection and cancer.” Scripps Research said the findings help explain why the drug may restore exhausted T cells while avoiding the severe inflammation associated with less targeted cytokine stimulation.
Teijaro’s lab is now studying whether pairing SAR’877 with anti-inflammatory drugs could further reduce side effects and permit higher dosing, according to Scripps Research. The clinical trial remains early, and the findings reported so far do not establish whether the drug will prove safe and effective for broader cancer treatment.
This story draws on original reporting from Medical Xpress.