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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - EN_ACTI2NG (European Network on Anti-Cancer Immuno-Therapy Improvement by modification of CAR and TCR Interactions and Nanoscale Geometry)

Teaser

Summary

Cancer is one of the main causes of death within Europe. Given the aging of the population it can be expected that the number of Europeans suffering cancer will increase in the coming years. It is therefore important to develop and optimize anti-cancer therapies. Recently immunotherapy against cancer, based on using a patientâ€™s own immune system to eradicate cancers, was introduced into the clinic. This approach has provided a qualitative change in the treatment of various cancers, leading to long term survival of patients whose life expectancy with more traditional therapies (radio- and chemotherapy) was much more limited. This therapy is still at its very early stages of development and needs to be optimized to reduce side effects and be expanded to more types of tumors. Europe is lagging as compared to the USA and China in the development of these therapeutic approaches, thereby missing out on important clinical and economic opportunities.

The EN-ACTI2NG network (European Network on Anti-Cancer ImmunoTherapy Improvement by Modification of CAR and TCR Interactions and Nanoscale Geometry) trains 10 early stage researchers in the development of immunotherapy approaches centered on genetic modification of the patientâ€™s white blood cells with receptors that can recognize the tumors. Scientific projects are aimed at 1) understanding the molecular mechanisms underlying the function of these receptors, in order to develop more rational ways of designing such receptors, 2) optimizing function by defining new formats and altering interaction modes of these receptors and 3) to isolate receptors recognizing new targets on the tumor cells, thereby expanding the clinical reach of this therapy. Via additional training in research techniques, career planning and communication skills and by performing secondments with research groups and companies that have complementary approaches the early stage researchers should receive a multidisciplinary education that should allow them to embark on a successful professional career in development or implementation of immunotherapy.

Work performed

The scientific projects have progressed according to plan. The projects centered on understanding the molecular mechanisms of function of tumor-specific receptors have developed the systems necessary to measure via high resolution flourescence microscopy the mobility, interaction and activation events of these receptors. Initial quantitative analysis indicate that even though these receptors can bind their targets very well they need many of these binding events to induce the activating events leading to killing of the tumor cells. This suggests that improvements in signaling capacity are warranted.

Projects focused on new formats of receptors have generated most of them via genetic engineering techniques and have expressed them in cell lines or white blood cells isolated from healthy volunteers and are testing them for their function in quantifiable in vitro experiments. Preclinical models, previously established by two of the particpating groups, are now being used to test such new recpeotrs in a clinically more relevant setting. Variants of molecules associating with tumor-recognizing receptors have been made as well and will be tested in conjunction with these receptors for their ability to improve the tumor killing capacity of the engineered white blood cells. In addition a unique approach within the field of modification of white blood cells with tumor specific receptors is being the developed, using DNA fragments (â€˜aptamersâ€™) that can bind these molecules, couple them to other receptors on the white blood cells or even facilitate a specific interaction with the tumor cell in order to improve the capacity of these white blood cells to kill the tumor cells. Several of such aptamers have been isolated and have been shown to improve the response of the white blood cells in in vitro experiments.

Finally, using genetic screening and in silico analysis new targets have been defined on various types of white blood cell-derived tumors. These targets can now be used to isolate white blood cells that are specific for these targets.

Final results

The development of tumor-specific receptors has so far been mostly guided by trial and error. The potential definition of quantifiable parameters that correlate with optimal function would make the design and testing of new receptors much more efficient. New formats of these receptors and new ways to have these receptors interact with their target cells should allow for better efficiency of these receptors, potentially even those already approved for clinical use. The already established procedures and infrastructure to move such receptors to clinical trials and the clinic makes it likely that any relevant improvements in receptor format and function resulting from the research program of the EN-ACTI2NG network could make it to their therapeutic application within a relatively short time frame.