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Immune DIREcted and Cancer-selective immunoTherapy

Periodic Reporting for period 1 - I-DireCT (Immune DIREcted and Cancer-selective immunoTherapy)

Reporting period: 2019-01-01 to 2020-12-31

The human immune system is highly effective in recognizing and eliminating threats to the human body. However, in the case of cancer the malignant cells have learned tricks to avoid recognition and/or elimination by the immune system. Indeed, it is critical for cancer cells to remain undetected in order to grow unrestricted, metastasize and cause havoc.

In recent years, researchers have uncovered various of the ways how cancer cells manage to escape the immune system. These can be divided into two main mechanisms. The first is that cancer cells exploit certain brakes that have been built in to the immune system in order to prevent autoimmunity. Cancer cells highly express such brakes and, analogous to braking in a car, this leads to the shut-down immune cells when they encounter a cancer cell. The second is that, in keeping to the car analogy, in order to get moving the driver of a car needs to hit the accelerator. In the case of cancer, the accelerator is absent. Consequently, an immune cell will encounter a cancer cell and be faced with too much braking and too little accelerating.

Based on these insights, scientists have developed therapeutics that can block the brakes or activate the accelerator on immune cells. Particularly the first strategy has in recent years revolutionized the treatment of various types of cancer, such as skin cancer, with long-term remission and cure of patients that previously had only weeks to months to live. Similarly, strategies to activate the accelerator have also shown promising activity in clinical trials.

However, curative treatment is still the exception and is restricted to a subset of tumour entities. Furthermore, the current approaches remove the brake or hit the accelerator throughout the body, which can lead to aberrant activation of immune cells throughout the body (Figure 1). Consequently, such therapies can lead to severe dose-limiting (auto)immune-mediated toxicity.

The objective of I-DireCT is to develop second-generation immunotherapeutics that remove the brake or hit the accelerator only at the site of the cancer.

Specifically, we will develop a set of new therapeutics that only become active in the tumour microenvironment. Secondly, we will encapsulate these new therapeutics into delivery systems that ensure that while these therapeutics are ‘en route’ they are incapable of interacting with the human body. Only at the site of the cancer, these delivery systems are engineered to release the active therapeutic and, hereby, reactivate the immune system to fight against the cancer (Figure 1).

I-DireCT is and integrated academia-industry approach that builds on the expertise of strong points uniquely positions to develop a set of improved next generation cancer immunotherapeutics that progress beyond the state-of-the-art.
The I-DireCT consortium has so far generated four different new therapeutics that have been evaluated in laboratory settings for the ability to remove the brake or hit the accelerator of immune cells only when encountering a cancer cell. The proof-of-concept that has been developed for these four drugs indeed demonstrated that the intended mode-of-action has been achieved. The lead therapeutic has currently entered early clinical evaluation in patients with epithelial cancers to assess the safety and preliminary evaluation of anticancer activity.

At the same time, several delivery systems have been developed within the consortium to have the intended property of releasing the therapeutic only at the site of a tumour. The first system for specific release has by now been established sufficiently in laboratory settings (and is accepted for publication by a peer-reviewed journal). Further steps to ensure the homing towards the site of the cancer are being currently evaluated.

To conclude, the development of both components needed to achieve the overall objective of I-DireCT is progressing rapidly and the integration of both systems is anticipated to the successful establishment of second-generation immunotherapy.
With the combined efforts of the academic and industrial partners, I-DireCT is expected to deliver new state-of-the-art immunotherapy. This therapy is designed to deliver and releases a tumour-selective therapeutic only in the tumour, with the aim of increasing both the efficacy as well as the safety of immunotherapy. This is clear step beyond the currently available therapeutics that ubiquitously activate the immune system throughout the human body.

The socio-economic impact of this progress is expected to be large, with new and potentially curative therapeutic options becoming available for hard-to-treat and deadly cancers such as epithelial ovarian cancer and Acute Myeloid Leukemia. Moreover, the concepts being developed within I-DireCT are more broadly applicable and may be of future use in other types of cancers.
I-DireCT science objective