An alternative approach to immunotherapy: A bispecific agonist

An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy

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Chan S et al. Nature Cancer 2022 March

In the past 20 years, oncology has been revolutionized by immune checkpoint blockade therapies, although they have shown variable efficiency in some indications. Another approach to immunotherapy is to boost T cell activation using agonists of costimulatory receptors, instead of blocking immune checkpoints. One target of choice for such approach is the glucocorticoid-induced tumor necrosis factor receptor-related protein, GITR. Although preclinical studies using GITR agonists showed promising results, early-stage clinical trials only demonstrated limited success for these compounds.¹ This limitation is believed to be due to the lack of potency of the compounds to induce receptor clustering, suggested to be a critical mediator of T cell activation.²

A novel bispecific agonist

A recent study,³ published in Nature Cancer in March 2022, tried an alternative approach by developing and testing a bispecific agonist, associating an anti-PD1 antibody with the agonist GITR-L, hence producing a PD1-directed GITR-L. This design should allow the specific and efficient targeting of PD1⁺GITR⁺ double-positive T cells.

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Efficient anti-tumor efficacy

The authors first performed in vitro studies confirming that GITR clustering is critical for optimal signaling. A murine surrogate was then tested in syngeneic models, and efficiently inhibited growth of both CT26 and EMT6 tumors. Treatment with the murine surrogate increased activated, memory and proliferating CD4⁺ and CD8⁺ T cells in the blood and tumors, while reducing T_regs and exhausted CD8⁺ in the tumor microenvironment. Chimeric compounds (anti-muPD-1-huGITR-L and anti-huPD-1-muGITR-L) were tested in WT and single Knockin human GITR and PD-1 homozygous genetically engineered mouse models, demonstrating the requirement of PD-1 and GITR co-engagement for efficient anti-tumor activity. The mechanism of action of the bispecific agonist was further described as CD8⁺ T cell dependent, not CD4⁺, thus differing from the mechanism of action of a GITR-L:anti-PD1 combination therapy. Last, pharmacodynamic studies in non-human primates demonstrated the compound’s efficacy in this species, suggesting good translatability.

An alternative approach to immunotherapy

These data show that a novel bispecific agonist specifically developed to direct GITR-L to PD1+ cells induces clustering of GITR through a FcγR independent mechanism and is thus a true T cell agonist. In addition, it has been shown to be more efficient than monotherapies, alone or in combination. This alternative approach in cancer therapy could be used with other immunotherapies in specific indications with low lymphocyte infiltrates, i.e., cold tumors.

Of note, the human GITR and PD-1 Knockin mouse models used in this study were designed and generated by genOway, a designer and provider of numerous physiologically relevant preclinical models in multiple research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

References:

1. Choi Y, Shi Y, Haymaker CL, Naing A, Ciliberto G, Hajjar J. T-cell agonists in cancer immunotherapy. J Immunother Cancer. 2020 Oct;8(2):e000966.
2. Garber K. Immune agonist antibodies face critical test. Nat Rev Drug Discov. 2020 Jan;19(1):3-5.
3. Chan S, Belmar N, Ho S, Rogers B, Stickler M, Graham M, Lee E, Tran N, Zhang D, Gupta P, Sho M, MacDonough T, Woolley A, Kim H, Zhang H, Liu W, Zheng P, Dezso Z, Halliwill K, Ceccarelli M, Rhodes S, Thakur A, Forsyth CM, Xiong M, Tan SS, Iyer R, Lake M, Digiammarino E, Zhou L, Bigelow L, Longenecker K, Judge RA, Liu C, Trumble M, Remis JP, Fox M, Cairns B, Akamatsu Y, Hollenbaugh D, Harding F, Alvarez HM. An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy. Nat Cancer. 2022 Mar;3(3):337-354.