UCLA researchers have discovered a therapy for anti-PD-1 resistant tumors in colon carcinoma patients. A small molecule therapeutic alone or in combination with immune-checkpoint blockade (ICB) therapy exhibits tumor remission even in sublines with mutated signalling pathways that have rendered them ICB resistant.
BACKGROUND:
Immunotherapy, the recruitment of T cells to induce an immune response at tumor sites, has rapidly emerged as an effective cancer treatment. This strategy relies on the capacity of cytotoxic T cell lymphocytes to recognize and selectively induce antitumor immune response. While objective clinical responses were observed for FDA approved therapies (monoclonal antibodies targeting T cell activation), the response is tempered by the overexpression of immunosuppressive ligands on the tumor cell surface. The hijacking of expression by tumors has led to the development of innate or adaptive resistance, which constitutes a significant limitation of immunotherapy as a treatment option. A prominent suppression mechanism involves the binding of the programmed death receptor 1 (PD-1) on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to the overexpressed programmed death ligand 1 (PD-L1) on tumor cells. Immune checkpoint blockade (ICB) strategies aim to block these binding events to restore immune response. Existing anti-PD-1 therapies have shown promise, yet resistance and/or immunity has begun to emerge in patients.
INNOVATION:
UCLA researchers performed loss of function mutations on two pathways identified in biopsies of patients resistant to anti-PD-1 therapies and tested strategies to overcome the resistance. Using CRISPR/Cas9 strategies they generated relevant knockout sublines of murine MC38 colon carcinoma, a model of high mutational load cancer that responds well to anti-PD-1. The significant antitumor activity of anti-PD-1 was lost in these knockout sublines and consequent mass cytometry analysis revealed that anti-PD-1 was unable to change tumor CD8 T cell infiltration. The researchers then identified a small molecule therapeutic (NKTR-214) that alone or upon co-administration with anti-PD-1 therapies significantly increased the survival rate. There is no prior description of any therapy that is active in cases of resistance to anti-PD-1 mediated by defined mutations in the two identified signalling pathways.
POTENTIAL APPLICATIONS:
- Immunotherapy
- Cancer therapy
ADVANTAGES:
- Effective against anti-PD-1 resistant tumors
- Selective for malignant cells
DEVELOPMENT-TO-DATE:
NKTR-214 alone or in combination with anti-PD-1 therapy has been validated in MC38 colon carcinoma lines and knockout sublines that are resistant to anti-PD-1 treatment.
Related Papers (from the inventors only):
Parisi, G., Saco, J.D., Salazar, F.B. et al. Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist. Nat Commun 11, 660 (2020). https://doi.org/10.1038/s41467-019-12901-3