Boosting Anti-Tumor Response: The Synergy of RG6333 and Glofitamab in Preclinical Studies

The abstract discusses the importance of T cell activation and effector functions in the immune response against cancer. It highlights that T cell receptor signaling, or "signal I," is essential but not sufficient; a second signal, "signal II," is also necessary, typically provided by costimulatory receptors like CD28. Glofitamab, a CD20-targeted bispecific antibody, is effective in treating relapsed/refractory non-Hodgkin Lymphoma (r/r NHL), but some patients do not respond to it alone. To enhance the response, RG6333, a CD19-targeted bispecific antibody with a unique CD28 binding moiety, is being studied. It provides a strong but safe "signal II" only in the presence of "signal I," avoiding single-agent activity and cytokine-release syndrome (CRS).

Preclinical experiments have shown that RG6333, even with reduced CD28 affinity, maintains its potency when combined with glofitamab in vitro and in humanized NSG mice. It does not induce T cell activation or cytokine secretion on its own, unlike TGN1412, a CD28 superagonist. A treatment regimen involving staggered infusions of glofitamab and RG6333 has been proposed for safety and potency. This combination has led to tumor-free outcomes in a difficult-to-treat tumor model and has been shown to boost T cell infiltration and prolong the response to glofitamab. Alternating RG6333 with another costimulatory agent, RG6076, has completely prevented tumor relapse during treatment. RG6333 also enhances cytokine secretion and T cell activation in patient samples.

The data support the combination of RG6333 with glofitamab for r/r NHL patients, offering a promising alternative to CAR-T cell therapies. RG6333 is currently being studied in a phase I clinical trial in combination with glofitamab.