Abstract 4981: Cisplatin and anti-CD70 therapy: Ideal partners in crime against NSCLC
Authors: Jacobs Julie , Deschoolmeester Vanessa , Zwaenepoel Karen , Rolfo Christian , Lardon Filip , Smits Evelien , Pauwels Patrick 
Published: July 2016

Introduction:

Upon interaction of CD70 with its receptor CD27, the NFκB pathway is activated, leading to proliferation and survival. Therefore, CD70 expression is tightly regulated and only transiently expressed on cells of the lymphoid lineage. Constitutive expression of CD70 by tumor cells can facilitate immune evasion by increasing the amount of suppressive regulatory T cells (Tregs), inducing T cell apoptosis and skewing T cells towards T cell exhaustion. Previously, we have detected CD70 positivity in non-small cell lung cancer (NSCLC) specimens, comprising patients that lack other targeted treatment options. This CD70 expression can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Furthermore, anti-CD70 therapy has the exciting potential to enhance antitumor immune responses by blocking Treg proliferation. In this study, we have focused on the combination of anti-CD70 therapy with chemotherapeutic agents, to increase tumor cytotoxicity.

Material and Methods:

The cytotoxic effect of cisplatin was evaluated on a panel of five NSCLC cell lines (CRL-2868, CRL-5908, CRL-5883, LUDLU-1, A549), differing in their genetic aberrations, histological subtype and expression of CD70. Based on these cytotoxicity experiments 3.5μM, 7μM and 13μM were considered low, medium and high concentrations of cisplatin respectively. Using flow cytometry, we tested the effects of cisplatin on the expression of membranous CD70 at different time points (1h, 6h, 24h, 48h). Next, we evaluated whether an induction in CD70 expression could increase the ADCC potential of anti-CD70 therapy using the xCELLigence RTCA technology. Finally, we assessed the immune stimulatory potential of this combination strategy by analysis of Treg proliferation as well as cytokine production.

Results:

Flow cytometric analysis demonstrated the highest induction of CD70 expression, 24 hours after treatment with 7μM cisplatin, reaching significance in 4/5 cell lines. Next, we assessed whether this increase in CD70 expression could intensify the ADCC effect of anti-CD70 therapy. CRL-5883, a CD70- cell line bearing no response to anti-CD70 monotherapy, showed a significant inhibition of proliferation after sequential administration of cisplatin and anti-CD70 therapy. Also, in A549 (weak CD70+) and CRL-5908 (strong CD70+), the combination of anti-CD70 therapy and cisplatin resulted in a significant decrease in cell survival compared to monotherapy. Also our immune data point towards a favorable effect of the combination.

Conclusion: Our preliminary data show that the combination of anti-CD70 therapy with medium doses of cisplatin significantly increases tumor specific cytotoxicity of the drug, compared to single treatment regimens. This combination strategy has the potential to reduce drug-related side effects and improve general outcome of NSCLC, still the most lethal type of cancer worldwide.

Citation Format: Julie Jacobs, Vanessa Deschoolmeester, Karen Zwaenepoel, Christian Rolfo, Filip Lardon, Evelien Smits, Patrick Pauwels. Cisplatin and anti-CD70 therapy: Ideal partners in crime against NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4981.