Oncology - New approaches to cancer therapy

Oncology - New approaches to cancer therapy

Cancer is the second most common cause of death in Germany. However, the prognosis has improved significantly in recent years. Science has made great strides in the search for new more effective and less invasive treatments. Our new dossier: Oncology - New Approaches to Cancer Therapy provides an overview.

1. Facts and figures

The numbers are alarming: in 2019, 502,655 people in Germany were diagnosed with cancer – 234,925 women and 267,730 men. These are the latest data from the Center for Cancer Registry Data (ZfKD) at the Robert Koch Institute (RKI). According to the data, about 4.6 million people in Germany currently have cancer, of which 2.55 million are women and 2.10 million are men. Due to improved survival rates and demographic aging, the number of cancer cases in Germany is increasing. In industrialized countries, about five percent of the population is now living with a cancer diagnosis. After cardiovascular diseases, cancer remains the second most common cause of death in Germany.

The new treatment options of recent years have made an impact: around two-thirds of those affected by a cancer diagnosis are now considered "long-term survivors", as their cancer diagnosis occurred five or more years ago. For 27% of all "cancer survivors," as many as 15 years or more have passed since diagnosis. Through the Center for Cancer Registry Data, it is possible to track trends in survival rates by individual cancer type. For black skin cancer, for example, the five-year survival rate has increased from less than 60% in the 1970s to about 90% today.

About half of all diagnosed cases can be attributed to three types of cancer: Breast cancer accounted for about one million of cancer survivors (22%), prostate cancer for about 710,000 (15%), and colorectal cancer for about 555,000 (12%).

Cancer in global perspective

The World Health Organization (WHO) groups major disease areas around the globe according to their impact on life expectancy. The disability-adjusted life years (DALY) indicator is defined as the sum of years of life lost due to death (YLL) and years of life lost due to health limitations (YLD). WHO estimates that approximately 300 million DALYs have been lost from the global population due to cancer. Although other diagnoses such as cardiovascular disease or infectious diseases have an even greater global impact on health, drug innovation by the biotechnology and pharmaceutical industries has focused much more on oncology in recent years.

One of the reasons for this is improved molecular diagnostics, described by the buzzword "personalized medicine". Fine, mutation-accurate analysis of the DNA sequence of cancer cells and healthy tissue, and hundreds of thousands of comparisons of patients' genome sequences with data from healthy individuals, have led to a much deeper understanding of the underlying molecular changes that cause a cancer cell to grow out of control. Other disease areas still lag behind in this regard, because what happens in the development of cardiovascular disease, for example, is usually influenced by many different factors rather than single mutations. Studies suggest that across all cancers, there are a total of only twelve metabolic and signaling pathways in which different mutations lead to uncontrolled cell growth, which is something the pharmaceutical industry needs to address (Vegas-Sanchez, 2018).

2. From antibodies to cell therapy: CAR-T and more

Cancer cells have the ability to make themselves "invisible" to the immune system. Put simply, this is because the immune system has evolved to recognize foreign invaders or to eliminate a cell infected with viruses. The cancer cell, on the other hand, appears relatively unchanged on the outside and becomes a problem primarily because of its uncontrolled growth. Scientists have spent decades trying to find a way to use the natural defenses of the body's immune system to fight out-of-control cancer cells. The first approach was to look for specific features on cancer cells (antigens) that could be targeted with antibodies. These activate the immune system (making the cancer cells "visible" again), which can then attack the cells covered with the antibodies. In this field, there are several approved drugs that directly target so-called tumor antigens. The company Heidelberg Pharma AG in Ladenburg has found a special solution to this problem. It attaches a cytotoxin (Amanitin, derived from the green tuberous leaf fungus) to these specific antibodies, which intensifies the attack on the cancer cell by also driving dormant or resistant cancer cells are driven to cell death. These so-called antibody-drug conjugates (ADCs, also known as chemoimmune conjugates) are currently being widely used as new cancer therapies. They are part of many drug pipelines in the biopharma industry.

With the realization that the cellular response of the immune system to the cancer cell is down-regulated via so-called checkpoints, a broad spectrum of applications opened up. Drugs known as checkpoint inhibitors have helped cancer therapy make tremendous progress. These checkpoint inhibitors target different molecules on cancer cells, T cells, and dendritic cells that abrogate the inactivity, making the cancer cell vulnerable to attack in the first place. This interplay of molecules and cell types is now becoming more complex as a variety of combinations are possible. No longer is just one treatment method or therapeutic agent used, but combinations of checkpoint inhibitors and specific tumor antibodies, as well as different sequences of drug delivery depending on the tumor indication.

Morphosys AG (FWB:MOR, Nasdaq:MOR), Martinsried, Germany, is also active in the field of combination therapies. Its antibody Tafasitamab (Monjuvi), which was approved in summer 2021, is used in combination with lenalidomide as second-line therapy against diffuse large B-cell lymphoma (DLBCL). This cancer is the most common form of non-Hodgkin's lymphoma in adults, accounting for 40% of all cases worldwide, and is characterized by rapidly growing malignant B cells in lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease, with approximately 40% of patients failing to respond to first-line therapy or relapsing thereafter. In the U.S., approximately 10,000 patients are diagnosed each year with relapsed or refractory DLBCL who are not eligible for autologous stem cell transplantation (ASCT). Tafasitamab/Monjuvi is a humanized, Fc-modified, cytolytic monoclonal antibody that recognizes the surface protein CD19 on B lymphocytes. The antibody is also being tested in other related diagnoses and is in several other clinical trials. With the acquisition of Constellation Pharma, Morphosys also acquired the compound pelabresib, an orally available small molecule to be used in combination with the current standard of care for the rare disease myelofibrosis, which is estimated to affect approximately 35,000 new cases annually in the United States and Europe. First results of the pivotal trial are expected in the first half of 2024.

Heidelberg-based Apogenix AG has focused on a different endogenous control system for the removal of tumor cells. The CD95-ligand, a member of the tumor necrosis factor family was identified years ago as a cell signal that drives tumor cells to cell death, known as apoptosis. But when tumors turn "invisible," they reverse this principle of action directed against them and send the attacking immune cells into cell death. The tumor cells remain unharmed and can continue to grow unhindered. Apogenix has engineered a fusion protein (Asunercept) that intercepts the tumor cell signals and maintains the activity of the immune cells, allowing them to proceed unimpeded to eliminate the tumor cells. Clinical efficacy has been confirmed in a Phase II study, and an international study is ongoing.

In addition to antibodies and active ingredients combined in different variants, there are also approaches that improve or enhance the interaction of certain cell types with the tumor cell. The approach of Heidelberg-based Affimed GmbH belongs in this field. With its "cell linker", the company relies on natural killer cells (NK cells). Their task - the elimination of infected or otherwise "degenerate" cells such as cancer cells - is actively suppressed by signal substances of the tumor tissue. Affimed has developed a bi-specific antibody as a linker molecule that recognizes one marker on the tumor cell and one on the NK cell and brings these two cells so close together that the NK cell can perform its task and kill the tumor cell. This matching of cells succeeds very specifically and very effectively. Although only tested in early phase I/II clinical trials to date, the results shown are extremely impressive.

Munich-based Micromet AG too had once developed such a linker, which was able to gain approval after its takeover by the US biotech company Amgen and has since given the field of cell-mediated immunotherapy a major boost.

CAR-T (Chimeric Antigen Receptor) cell therapy, which is growing in importance, uses cells that are even more directly directed against the tumor, namely modified immune cells of the patient. It is a cancer immunotherapy that uses genetically engineered T cells with synthetic antigen-specific receptors. When the first two CAR-T cell therapies were approved in Europe in 2018, they gave seriously ill patients with certain blood cancers a chance of long-term survival - and even cure.

Starting with the blood collection, the genetic engineering of the body's own immune cells, and the infusion of these "CAR-T" cells, the novel procedure had to overcome several challenges in logistics, storage, and modification of the patient's cells, and its own standards had to be developed. Today, about 520 hospitals worldwide are accredited to international standards for the use of CAR-T cell therapies. Leading the way are the United States (223), the United Kingdom (49) and Italy (45) - followed by Germany (40).

Currently, six such cell preparations are already approved in Europe. And the range they cover is expanding. Clinical trials are underway for other forms of blood cancer such as diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), mantle cell lymphoma or multiple myeloma.

At German university hospitals, this form of cell therapy is not only being applied, but also expanded and adapted in a variety of ways and tested in combination with other therapeutics. Even beyond oncology, an area of application for CAR-T has been discovered in autoimmune diseases at the Erlangen-Nuremberg Hospital. Several listed biotech companies are also active in this field and have their own modifications of cell therapy in (mostly still early) clinical development.

Medigene AG, (FWB:MDG1), based in Martinsried, focuses on T cell-targeted immunotherapies. The lead program MDG1015, a TCR-T therapy for the treatment of various solid tumors, is in preparation for a clinical trial application. Good results have already been achieved with MDG1011 in a Phase I/II clinical trial in blood cancer. In TCR-T therapy, T-cells are taken from the patients and their T-cell receptor is modified to recognize antigens on the tumor cell that match the cancer in question and to attack this cancer cell more effectively. Medigene has its own technology platform with which these special tumor antigens and matching T cell receptors can be developed.

A similar but technologically different approach is being pursued by the Tübingen-based company immatics, whose drug candidate IMA203CD8 has been undergoing clinical trials in patients since the summer. The T-cell receptor approach targets very specifically identified tumor antigens and combines them with additional molecules designed to bring the so-called cytotoxic T cells (CD8-positive cells) even closer to the tumor tissue. This CD8 coreceptor plays an important role in the recognition of antigens by T cells as well as in T cell activation, allowing both CD8 and CD4 T cells to effectively participate in the anti-tumor response. With the cell therapy candidate IMA203CD8, immatics aims to further improve the strength and duration of the anti-tumor response as well as the clinical success of TCR-T therapies against a specific target structure in solid tumors. As this target structure occurs in a variety of solid tumors, a broad patient population could be reached.

3. Radiopharmacy

Nuclear medicine is a medical specialty that uses targeted radiopharmaceuticals to image and treat disease. These contain radioactive particles, also known as radionuclides. The coupling process of a radionuclide to a molecule is known as labeling or radiolabeling. Different radioisotopes can emit different types of radiation, such as alpha, beta, or gamma radiation, and each can be used in a different clinical setting. Alpha and beta radiation does not have a very long range, but it is intense. It is primarily used for treatment because it can damage and kill diseased cells without causing damage to surrounding tissue.

In the combination of differently radiating radionuclides, it is possible to switch from imaging to locally effective radiation therapy, thus linking diagnosis and therapy in a molecular way. The artificial term theranostics has become established for this. In nuclear medicine, theranostics refers to the use of carrier molecules labeled either with radionuclides for diagnostic imaging, for example with positron or gamma emitters, or radionuclides for the treatment of a specific disease.

Large pharmaceutical companies such as Novartis are particularly active in this area and have greatly increased the overall importance of radiopharmaceuticals in the public perception through acquisitions. In addition, new approvals are pending, and in this slipstream some German companies have also moved more into the spotlight.

Berlin-based Eckert & Ziegler Strahlen- und Medizintechnik AG offers isotope technology components for nuclear medicine and radiotherapy. The company also has services and products in the field of radiopharmacy from early development to commercialization in its portfolio and uses its isotope products not only in the health sector, but also in the metrological analysis of exploration activities in the oil and gas industry. The Eckert & Ziegler share (ISIN DE0005659700) is listed in the SDAX of the German Stock Exchange. With annual sales of over € 200 million, more than 900 employees and a growing site in China/Asia, the company is well equipped for the overall growing radiopharmaceutical market.

Another company in this field is Isotope Technologies Munich SE (ITM), founded in 2004. It develops and produces medical radioisotopes as well as cancer therapies and diagnostics that fall under the heading of "theranostics": The radioactive isotopes of the Munich can be combined with molecules can combine certain radioactive isotopes with molecules that bind specifically to the tumor, inducing tumor-specific local cell death. Other isotopes are used to support the appropriate diagnostic imaging, which also allows the use and effect of the therapy to be monitored. ITM has been producing radioisotopes for pharmaceutical companies around the world since the company was founded. In addition, the company, which now employs around 460 people, has developed its own product pipeline for the targeted treatment of cancer, with ITM-11 (n.c.a. 177Lu edotreotide) being the most advanced targeted radionuclide therapeutic. In October, the Company announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for ITM-11 (n.c.a. 177Lu-edotreotide), a radiopharmaceutical product candidate for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). ITM-11 is currently being evaluated as Targeted Radionuclide Therapy in two Phase III clinical trials (COMPETE and COMPOSE) in patients with varying severities of currently particularly poorly treatable pancreatic tumors. Fast-track status allows ITM to work closely with the FDA to optimize and expeditiously advance the final steps in the development of ITM-11 to make the radiopharmaceutical product candidate available to patients with GEP-NETs as soon as possible. ITM is privately held by a small number of investors, including US VC investor Petrichor since early 2021. In total, ITM has been able to raise around €170m in several financing rounds over the past 18 months.

4. The mRNA vaccination

Scientists have been researching mRNA therapies for serious diseases for years. BioNTech, which developed the first mRNA-based vaccine Corona, is testing therapeutic mRNA vaccines against various cancers, including colorectal cancer. The Mainz, Germany-based company, founded in 2008, originally began with cancer research. Corona was just a sideline, and now the company plans to refocus on cancer drug development. The corporation, now operating under EU law, has launched several Phase II trials for 2021, including one with an mRNA cancer vaccine for colorectal cancer. Here, the mRNA does not have components of a virus programmed into it, but rather protein components of the specific type of cancer to be vaccinated against. To produce the vaccine, the specific neoantigens of the tumor must first be identified. The most promising ones are then selected from these. A vaccine is then produced that is tailored to the cancer of the particular patient. BioNTech has developed the first "on-demand production process" of its kind for this purpose. The advantage of the mRNA is that it can be quickly adapted as tumor changes progress in a later phase of the disease. This is still a thing of the future, and so far no clear picture of the efficacy of this therapy has emerged from any clinical trial conducted by various developers. At BioNTech, the relevant data are not expected for some time.

Many other German biotechnology companies in the medical field are working on new cancer therapies. Some of these private companies have been able to raise large amounts of debt capital because their approach is considered particularly promising. These include the berlin-based cell therapy company T-knife Therapeutics, Catalym GmbH from Würzburg/Martinsried, Abalos Therapeutics GmbH in Düsseldorf, which is modifying a specific virus to be effective against solid tumors in a targeted manner, and Emergence Therapeutics AG in Duisburg, which is developing a highly targeted antibody-drug conjugate.