Background
Botensilimab, a multifunctional Fc-enhanced anti-CTLA-4 antibody, promotes superior T cell priming, memory formation, intratumoral regulatory T cell (Treg) depletion, and antigen-presenting cell (APC) activation, compared to first-generation IgG1 CTLA-4 antibodies. In patients with advanced solid tumors, botensilimab +/- balstilimab (anti-PD-1), demonstrates durable clinical responses across nine different immunotherapy-resistant or poorly immunogenic tumor types. To further deepen and broaden the efficacy of botensilimab to ‘cold’ and immunotherapy-refractory cancers, combination strategies with other therapeutic modalities targeting tumor-intrinsic factors, as well as pro- or anti-tumor immune cells, were explored across multiple preclinical models.
Methods
The efficacy of a mouse surrogate (ms) of botensilimab, alone or combined with other modalities, was assessed in syngeneic mouse models of PD-1 resistant glioblastoma (GL261), breast cancer (4T1), pancreatic ductal adenocarcinoma (KPC), melanoma (B16) and colorectal cancer (CT26). Tumors were implanted orthotopically or subcutaneously. Combination agents/modalities included focal radiotherapy, chemotherapy (doxorubicin, etoposide, gemcitabine and nab-paclitaxel), iNKT activation (αaGalCer), QS-21 saponin adjuvant, vaccines, ENPP1 inhibitor and immune checkpoint/co-stimulatory therapy (anti-PD-1 and anti-CD137 agonist antibodies). Tumor growth kinetics and survival were monitored. In a subset of studies, correlative immune response phenotyping was conducted.
Results
In PD-1 resistant GL261 models, botensilimabms combined with focal radiation or doxorubicin plus anti-PD-1 demonstrated superior efficacy compared to either monotherapies. In the botensilimabms/doxorubicin/anti-PD-1 combination study, efficacy correlated with increased CD8+ T and NK cell infiltration, activated APCs and reduced Tregs. In the CT26 model, combination of botensilimabms with an ENPP1 inhibitor, SR-8541A, produced superior tumor growth inhibition compared to the respective individual therapies, and was associated with enhanced T cell infiltration. Intratumoral injection of QS-21 saponin combined with systemic botensilimabms and anti-PD-1 promoted superior control of 4T1 lung metastases than either monotherapies. Mouse and human macrophage exposed to doxorubicin or QS-21 saponin upregulated FcRIV and FcRIIIA, respectively. In KPC tumor-bearing mice, botensilimabms combined with iNKT activation and chemotherapy to control tumor growth, superior to either monotherapy. Additionally, in B16 models, botensilimabms combined with etoposide and αPD-1 mAb, viral vectored neoantigen vaccines or anti-CD137 enhanced anti-tumor immunity and promoted long term survival.
Conclusions
These studies highlight the versatility of botensilimab to combine with a broad range of therapeutic agents and modalities to enhance anti-tumor immunity in difficult-to-treat mouse tumor models. Clinical trials exploring botensilimab combinations are ongoing.