Cancer therapy made to measure

“A nineteen-year-old medical student with leukemia was our first patient – I’ll never forget him.” With these words, Professor Marion Subklewe recalls the moment which she sees as a milestone in cancer therapy: Six years ago, she used individually gene-modified immune cells on a patient for the first time at LMU University Hospital – the method, which goes by the name of CAR T-cell therapy, utilizes activates the immune system to combat tumors.

In CAR T therapy, doctors extract T cells from patients and genetically modify them. They engineer these immune cells – a type of white blood cell – to recognize and destroy tumor cells. This is done by introducing a special gene into the T cells that encodes a so-called chimeric antigen receptor (CAR), which recognizes specific proteins (antigens) on the surface of the cancer cell.

Clinical practice and research closely interlinked

“When the first studies about CAR T cells appeared in 2013, I was instantly excited by the prospect that they could be even more effective than the therapeutic vaccine strategies against cancer which I was pursuing at the time,” recounts Subklewe, who is Professor of Internal Medicine with a special focus on cellular immunotherapy. Alongside her role as senior physician at LMU University Hospital, she heads the Translational Cancer Immunology research group at LMU’s Gene Center Munich. This allows her to closely link clinical practice and research and to continuously advance the development of the method.

In the meantime, the treatment has come a long way. At the beginning, all patients were intensively monitored around the clock, while today they are treated in a general ward for the most part. Although serious side effects such as cytokine release syndrome (CRS) and neurotoxic effects continue to occur, the proportion of affected patients has significantly decreased. “Now we’ve got good options for counteracting this,” says Subklewe. Her research has shown that the most common longer-term side effect is increased susceptibility to infection among people who’ve undergone the treatment. The fitness of the patient also plays a role in their prognosis, as evaluations of patient data have revealed. “So we launched a sports program to get patients fitter before cell therapy.”

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New approaches for complex tumors

In the laboratory, Subklewe is working on the further development of immunotherapy against cancer. “A big passion of mine is bringing CAR T-cell therapy to bear on tumor types that are not yet treatable, in particular acute myeloid leukemia (AML).” CAR T-cell therapies are currently effective above all for certain forms of blood cancer that originate from B lymphocytes, such as acute lymphoblastic leukemia (ALL) and multiple myeloma. These cancer cells carry specific antigens on their surface, to which CAR T cells can bind in targeted fashion. Although this also destroys healthy B cells, the resulting loss can be equalized with drugs.

With AML, this is more difficult: Here, the blood-forming stem cells are themselves pathologically altered. A CAR T therapy would therefore also destroy healthy blood formation. Furthermore, the typical target structures to which CAR T cells bind in B-cell leukemias are lacking on these cells, while possible alternatives occur on other cells – which would lead to severe side effects.

»A big passion of mine is bringing CAR T-cell therapy to bear on tumor types that are not yet treatable.«

Marion Subklewe

This could be improved by the adapter CAR-T cell therapy developed by Subklewe: in this approach, the CAR-T cells are activated only when adapter molecules link them to tumor cells. These adapters could target various structures and are broken down in the body within around 30 minutes – allowing doctors to control the therapy. “It’s an interesting concept, which we would like to test for applicability and tolerability in a phase 1 study,” says Subklewe.

Focus on solid tumors

Another challenge is solid tumors, such as cancers arising from the pancreas, lungs, or liver. These tumors are harder to access for CAR T cells than the hematopoietic system, the natural ‘habitat’ of T cells. Moreover, solid tumors are very heterogeneous and few suitable target structures have been identified to date. “They grow out of the organs and often develop over many years and decades. Consequently, the tumor cells have a lot of time to evolve, such that in the end we often find very different cells there,” explains Sebastian Kobold.

Kobold is Professor of Experimental Immunooncology and deputy director of the Division of Clinical Pharmacology at LMU University Hospital. “The immune system can have both positive and negative effects when it comes to cancer – I’m fascinated by this Janus-faced character and by the possibilities of cell therapy,” he says. In his laboratory, Kobold investigates the fundamental mechanisms by which the immune system combats cancer and seeks ways of improving therapeutic cells. Primarily, the immunooncologist does preclinical work in the laboratory in order to test new approaches. “The principles are probably similar for many diseases,” he emphasizes. Accordingly, he is researching various solid tumors, including pancreatic, colorectal, breast, liver, and black skin cancers.

»The immune system can have both positive and negative effects when it comes to cancer – I’m fascinated by this Janus-faced character and by the possibilities of cell therapy.«

Sebastian Kobold

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DNA origami as scaffolding

“However, we also work extensively with hematological diseases,” says Kobold. “In doing so, we focus primarily on those in which CAR-T cell therapies have not been effective so far.” His research and Marion Subklewe’s research on immunotherapy for tumors complement each other, and the two researchers cooperate on various projects. Similar to Subklewe’s adapter CAR-T cell therapy, he also relies, among other approaches, on a system in which flexible structures — so-called PTEs (programmable T-cell engagers) — act like adapters that link the T cell to the tumor cell and activate it."

The scaffolding of the PTEs is created using DNA origami, a nanotechnology in which self-folding strands of DNA bind together. Then, various antibodies which specifically bind to tumor cells or T cells can be mounted on the scaffold. Kobold has already demonstrated in an in vivo model that PTEs work in a living organism. “The clever part of this technology would be that it could ultimately be made switchable, so that the interaction occurs only in the context of the cancer cell and not in that of healthy cells.”

Scalable therapies as cost-effective solution

The approach of attacking tumors through various target structures – whether via adapter molecules or by CAR T cells directly recognizing multiple target structures – has major advantages, because tumor cells can outfox the immune system by means of immune escape mechanisms. This includes, for example, downregulating certain target structures or employing immunosuppression mechanisms. “Even T cells can suffer from burnout and become exhausted,” observes Subklewe. The researchers are working on modulating the immune system such that the T cells remain effective for as long as possible. An innovative approach that is currently being tested in a phase 1 study equips CAR T cells with additional functions: They could then act as a ‘micro-pharmacy,’ releasing immunomodulatory messenger molecules which activate the immune system specifically at the tumor site – with minimal systemic side effects.

“I think we’re on a good track overall,” summarizes Kobold. “We understand the biology and immunology of these tumors better, and even with solid tumors we’ve seen that T cells can make an important contribution.” Nevertheless, he notes that the cost effectiveness of therapies is an important question. So-called universal stem cells are an approach that could make therapy more cost-effective and therefore more widely usable. These cells are engineered in such a way that they no longer suit just one patient only, but could be generated for a large number of people.

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AI analysis of patient data for more precise therapy recommendations

But which patient benefits from which therapy? “There are studies with positive results for solid tumors like pancreatic, stomach, and skin cancer,” explains Kobold. “But whereas the treatment works very well on some patients, it doesn’t help others at all. A single approach for all is probably not the right solution.”

Computerized approaches could point the way forward, the two researchers are convinced. As part of his ERC project CATACLIS, for example, Kobold is already using large patient datasets and machine learning to recognize patterns and progress the development of therapies. The primary focus to date has been on transcriptomes – that is to say, the analysis of mRNA – and this work has yielded important insights into the molecular mechanisms.

“With AI, we can pool a huge range of different parameters and consider tumor-related, patient-related, and immune-system-related factors in conjunction so as to derive the best individual therapy recommendation for the patient,” Marion Subklewe looks to the future. In this way, therapy decisions could be flexibly adapted and risks could be weighed dynamically. At any rate, the patient would remain at the heart of this process, emphasizes Subklewe: Benefits, risks, and opportunities must be discussed together to arrive at the best decision for each and every patient.

Prof. Dr. med. Marion Subklewe is senior physician at LMU University Hospital and heads the Translational Cancer Immunology research group at LMU’s Gene Center Munich.

Prof. Dr. med. Sebastian Kobold is Professor of Experimental Immunooncology and deputy director of the Division of Clinical Pharmacology at LMU University Hospital.

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