Georgina Kolcun

Immune checkpoint blockade has proved to be an auspicious therapeutic strategy in the field of cancer immunotherapy. Immune checkpoints are points at which the immune system may either stimulate or inhibit its immune response. The immune system may feel the need to heighten its response at the threat of foreign molecules and in contrast, may reduce its response in pursuit of self-tolerance. Tumor cells predominantly employ the use of immune inhibitory pathways which allows them to disguise themselves as self-cells by exploiting the phenomenon of immune tolerance. The most actively studied inhibitory pathways targeted in cancer immunotherapy are cytotoxic T‑lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) receptors. Both pathways limit autoimmunity, but CTLA4 suppresses T cell activation at the early stages while PD1 restricts effector T cell activity within peripheral tissues, usually at the later stages of tumor growth during inflammation.^1-3 Antibodies directed against CTLA4 and PD1 have shown promise against a variety of cancers including melanoma.⁴ It has been observed that concurrent use of these inhibitory antibodies enhances anti-tumor immunity.  Combination immunotherapy relies on a strong interplay between IL-7 and IFN-γ.⁵ IL-7Rα deficiency or IL-7 blockade results in a significantly reduced response to combination therapy. Therefore, the supplementation of IL-7 may increase the downstream signaling between IL-7 and IFN-γ and improve the efficacy of combinatorial therapy.⁵ While IL-7 and IFN-γ are both necessary to mediate combinatorial therapy, it is sufficient for IFN-γ alone to stimulate anti-CTLA4 effects. Melanoma tumors with loss of IFN-γ signaling lack a response to anti-CTLA4 therapy. This finding holds true in animal studies, where mice with IFN-γ receptor 1 (IFNGR1) knockdown tumors were associated with a high mortality, despite anti-CTLA-4 therapy.⁶ The combinatorial effect of PD1 and CTLA4 blockers has been structurally determined to have a collaborative effect based their respective, distinct interactions.⁷ The knowledge of their precise epitopes sheds light on the possibility to improve current therapeutic antibodies and develop more effective immunotherapy strategies, such as nanobodies. The interaction between anti-PDL1 nanobody “KN035”, human PD1, and PDL1 has a very high binding activity as compared to current anti-PDL antibodies and holds promise for the optimization of future immune regulators.⁸ Phase I clinical trials of concurrent therapy of anti-PD1 antibody Nivolumab and anti-CTLA antibody Ipilimumab in patients with advanced melanoma has suggested a better prognosis for patients with advanced melanoma than treatment with either agent alone.⁹

1. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39:98-106.
2. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer. 2012;12:252-264.
3. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.
4. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
5. Shi LZ, Fu T, Guan B, et al. Interdependent IL-7 and IFN-[gamma] signalling in T-cell controls tumour eradication by combined [alpha]-CTLA-4 [alpha]-PD-1 therapy. Nature Communications. 2016;7.
6. Gao J, Shi LZ, Zhao H, et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell. 2016;167(2):397-404. e9.
7. Lee JY, Lee HT, Shin W, et al. Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy. Nat Commun. 2016;7:13354.
8. Zhang F, Wei H, Wang X, et al. Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade. Cell Discovery. 2017;3:17004.
9. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133.