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CD27: An Emerging Target for Cancer Immunotherapy

Aliyah Weinstein, Ph.D.

Immune checkpoint molecules such as CTLA-4, PD-(L)1, and CD27, are a common target of immunotherapies against solid tumors. Targeting these molecules leads to the (re)activation of an immune response against a tumor, typically by blocking an inhibitory signal coming into the immune cell from either tumor cells or suppressive immune cells within the tumor microenvironment. The most well-known and earliest targets of checkpoint immunotherapies, targeting the PD-1/PD-L1 and CTLA-4 pathways, follow this mechanism and are known as checkpoint blockade immunotherapies. Immunotherapies that target CD27 function differently.

CD27 is expressed on conventional naïve and memory T cells, gamma-delta T cells, and effector and helper T cells immediately following antigen exposure but not at later stages of the primary immune response1,2. CD27 is also expressed on B cells and NK cells, the other immune cells of lymphocytic origin. The ligand for CD27 is CD70, which is also expressed on T cells as well as B cells and dendritic cells. Both of these molecules belong to the TNF superfamily; CD27 is also known as TNFRSF7 and CD70 as TNFSF7. The interaction between CD27 and CD27 provides activation and proliferation signals to the CD27-expressing T cell2,3.

Unlike checkpoint blockade immunotherapies, immunotherapies targeting CD27 are typically agonistic. These therapies include agonistic anti-CD27 antibodies or CD704. In a model of B cell lymphoma, treatment with an agonistic anti-CD27 antibody led to increased production of CCL3, CCL4, and CCL5, chemokines that recruit myeloid cells, by T and NK cells5. The myeloid cells recruited to the tumor site were phagocytic and capable of attacking the lymphoma cells. CD27 agonists have also made it into human clinical trials for hematologic cancers6. A small phase 1 clinical trial in lymphoma resulted in one patient with a complete response to therapy and three patients with stable disease. Furthermore, some of the patients who responded to therapy displayed CD27- tumor cells but CD27+ immune infiltrates, suggesting that agonizing CD27 is an effective therapy when it can act on intratumoral immune cells.

However, some hematologic cancers express CD27, in which case antagonistic anti-CD27 treatments are desirable. An antibody targeting human CD27 competes with CD70 for binding on tumor cells, inhibiting their proliferation, while activating T cells as a "signal 2" to TCR stimulation7.

Targeting the CD27/CD70 pathway is also being investigated in solid tumors. A phase 1/2 trial of anti-CD27 agonist in combination with the anti-PD-1 immunotherapy nivolumab showed that about half of patients had a partial response or stable disease, and this was correlated with increased presence of CD8+ T cells within the tumor microenvironment8. A phase 2 clinical trial looking at CD27 agonism as a therapy for non-small cell lung cancer is underway. While studies into immunotherapies targeting CD27 are ongoing, it is a promising target that may function best in combination with other immunotherapies9.

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References

1. Watts TH (2005) TNF/TNFR FAMILY MEMBERS IN COSTIMULATION OF T CELL RESPONSES. Annual Review of Immunology 23:23–68.

2. deBarros A, Chaves-Ferreira M, d’Orey F, Ribot JC, Silva-Santos B (2010) CD70-CD27 interactions provide survival and proliferative signals that regulate T cell receptor-driven activation of human γδ peripheral blood lymphocytes. European Journal of Immunology 41:195–201.

3. Polak ME, Newell L, Taraban VY, Pickard C, Healy E, Friedmann PS, Al-Shamkhani A, Ardern-Jones MR (2012) CD70–CD27 Interaction Augments CD8+ T-Cell Activation by Human Epidermal Langerhans Cells. Journal of Investigative Dermatology 132:1636–1644.

4. Buchan SL, Rogel A, Al-Shamkhani A (2018) The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood 131:39–48.

5. Turaj AH, Hussain K, Cox KL, Rose-Zerilli MJJ, Testa J, Dahal LN, Chan HTC, James S, Field VL, Carter MJ, Kim HJ, West JJ, Thomas LJ, He L-Z, Keler T, Johnson PWM, Al-Shamkhani A, Thirdborough SM, Beers SA, Cragg MS, Glennie MJ, Lim SH (2017) Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment. Cancer Cell 32:777–791.e6

6. Ansell SM, Northfelt DW, Flinn I, Burris HA, Dinner SN, Villalobos VM, Sikic BI, Taylor MH, Pilja L, Hawthorne TR, Yellin MJ, Keler T, Davis TA (2014) Phase I evaluation of an agonist anti-CD27 human antibody (CDX-1127) in patients with advanced hematologic malignancies. Journal of Clinical Oncology 32:3024–3024.

7. Vitale LA, He L-Z, Thomas LJ, Widger J, Weidlick J, Crocker A, O’Neill T, Storey J, Glennie MJ, Grote DM, Ansell SM, Marsh H, Keler T (2012) Development of a Human Monoclonal Antibody for Potential Therapy of CD27-Expressing Lymphoma and Leukemia. Clinical Cancer Research 18:3812–3821.

8. Sanborn RE, Pishvaian MJ, Callahan MK, Weise AM, Sikic BI, Rahma OE, Cho DC, Rizvi NA, Bitting RL, Starodub A, Jimeno A, Yellin MJ, Rawls T, Vitale L, Halim A, Zhang H, Keler T (2018) Anti-CD27 agonist antibody varlilumab (varli) with nivolumab (nivo) for colorectal (CRC) and ovarian (OVA) cancer: Phase (Ph) 1/2 clinical trial results. Journal of Clinical Oncology 36:3001–3001.

9. Starzer AM, Berghoff AS (2020) New emerging targets in cancer immunotherapy: CD27 (TNFRSF7). ESMO Open 4:e000629.