Clinical data from from an ongoing Phase I/II study of DKN-01, being developed by Leap Therapeutics, in combination with pembrolizumab (Keytruda?; Merck/MSD) in patients with advanced esophagogastric cancer, presented at the annual congress of the European Society for Medical Oncology – ESMO 2018, taking? place October 19-23, 2018 in Munich, Germany, confirms promising clinical activity.

DKN-01 is a humanized monoclonal antibody targeting the Dickkopf-related protein 1 or DKK-1 protein. This investigational agent is in clinical trials in patients with gastroesophageal cancer and biliary tract cancer, with an emerging focus on patients with defined mutations of the Wnt pathway and in combination with immune checkpoint inhibitors such as pembrolizumab.

Blocking immunity
DKK1, an inhibitor of Wnt/beta-catenin signaling, regulates the canonical and non-canonical Wnt cell signaling pathways. Aberrant Wnt signaling is often implicated in cancer, enabling cancer cells to grow and divide and to suppress the immune system. [1]

Research has shown that DKK1 maintains an environment around a tumor that suppresses the immune system’s ability to clear the tumor and to prevent metastasis.

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Furthermore, DKK1 has been shown to activate the suppressive effects of myeloid-derived suppressor cells, also known as MDSC, a type of white blood cell that can potently block other immune system cells.

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Published data confirms that metastatic tumor cells with stem cell-like features avoid the immune system by overexpressing DKK1 and secreting it out of the cell. In turn, secreted DKK1 can then down-regulate certain molecules on tumor cells known as natural killer (NK) cell activating ligands, or NK ligands, that would activate the immune system, causing these cancer cells to remain invisible to and evade the immune system. Through these multiple activities, researchers have confirmed that DKK1 helps protect the cancer cells from being targeted by the immune system. As such, DKK1 appears to increase tumor growth and metastasis and its elevated expression correlates with a poor prognosis in a range of cancers. [1][2]

Inhibition of DKK1
In preclinical models, inhibition of DKK1 has demonstrated anti-tumor activity.

For example, researchers have confirmed that anti-DKK1 inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Furthermore, tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice.

Based on this observation, researchers hypothesis that inhibiting DKK1 generates both a direct anti-tumor effect, as well as generate an immune anti-tumor response in a number of specific cancers, including the majority of lung cancers and esophageal squamous cell carcinomas (ESCC).[3]

Combination therapy
To date, the combination of DKN-01 and pembrolizumab has demonstrated promising clinical activity with a 23.5% overall response rate and 58.8% disease control rate in evaluable gastric or gastroesophageal junction cancer patients who have been heavily pretreated and have not had prior anti-PD-1/PD-L1 therapy (PD-1/PD-L1 na?ve).

Image 1.0: The immune system is divided into innate and adaptive immunity. Innate immunity refers to nonspecific defense mechanisms that defend the body immediately or within hours of an antigen’s appearance. These mechanisms include physical barriers such as skin, chemicals in the blood, and immune system cells that attack foreign cells in the body. The innate immune response is activated by chemical properties of the antigen. In contrast, the adaptive immunity refers to antigen-specific immune response, which is more complex than the innate immunity. The antigen first must be processed and recognized. After an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity also includes a “so called memory that makes future responses against a specific antigen more efficient. Recent data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms.[4]
The combination has generated durable responses in subgroups less likely to respond to pembrolizumab monotherapy.? This includes, for example, patients whose tumors are microsatellite stable (MSS) and/or PD-L1 negative.

The combination of DKN-01 and pembrolizumab may have additive clinical benefit through the targeting of both innate and adaptive immunity. Data to date suggest that elevated tumor expression of DKK1 may correlate with better patient outcomes. Biomarker analyses are underway to guide future clinical development in gastroesophageal malignancies.

Clinical Trial
The esophagogastric cancer clinical trial (P102) is a multipart study of DKN-01 as a monotherapy and in combination with paclitaxel or pembrolizumab.

The arm evaluating DKN- 01 plus pembrolizumab includes both dose escalation and dose confirmation cohorts and is designed to assess the safety, pharmacokinetics and efficacy of the combination. Data from the monotherapy and paclitaxel arms of the study have been presented previously and will be updated later in the year.

As of the September 26, 2018 cut-off date for the presentation, forty-five patients have been enrolled in the DKN-01 plus pembrolizumab study, thirty-eight PD-1/PD-L1 na?ve and seven refractory to PD-1/PD-L1 therapy. Two of the patients were enrolled in the 150mg DKN-01 dose, and forty-three patients at the 300mg DKN-01 dose. Leap expects that the PD-1/PD-L1 na?ve group will complete enrollment before the end of 2018.

All responding patients in the study had MSS tumors.

The overall response rate for pembrolizumab monotherapy in gastric or gastroesophageal junction patients with non-microsatellite instability high tumors in the KN-059 (n = 167) and KN-061 (n = 281) studies was 9.0% and 9.3%, respectively.

When this study is complete, Leap expects to choose an indication for a larger, controlled clinical study.

Reference
[1] Kagey MH, He X.Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. Br J Pharmacol. 2017 Dec;174(24):4637-4650. doi: 10.1111/bph.13894. Epub 2017 Jul 7
[2] Sato N, Yamabuki T, Takano A, Koinuma J, Aragaki M, Masuda K, Ishikawa N, et al. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010 Jul 1;70(13):5326-36. doi: 10.1158/0008-5472.CAN-09-3879. Epub 2010 Jun 15.
[3] Yamabuki T, Takano A, Hayama S, Ishikawa N, Kato T, Miyamoto M, Ito T, et al. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007 Mar 15;67(6):2517-25.
[4] Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ.Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235-71. doi: 10.1146/annurev-immunol-031210-101324.


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