CRI Speaks with 2021 Lloyd J. Old Award Recipient Dr. Ton Schumacher

In April, the Cancer Research Institute (CRI) and the American Association for Cancer Research (AACR) honored Ton N. Schumacher, PhD, of the Netherlands Cancer Institute and Leiden University Medical Center, with the 2021 AACR-CRI Lloyd J. Old Award in Cancer Immunology, which recognizes scientists whose research has had a major impact on the cancer field.

Throughout the past thirty-plus years, Schumacher has explored a fundamental question in immunology: how do T cells “see” other cells and determine whether they are normal or not? His discoveries—and the technologies he has created to make those discoveries—have had far reaching implications. Overall, his career contributions have refined our understanding of T cell recognition of cancer cells and enabled us to dissect these interactions more deeply, contributing to our efforts to treat cancer in humans.

Prior to this career award, Schumacher received a number of honors, including CRI’s William B. Coley Award in 2016 and election as an AACR fellow this year. He is currently a senior faculty member at the Netherlands Cancer Institute, a professor of immunotechnology at the Leiden University Medical Center, and a member of the CRI Scientific Advisory Council.

Recently, I spoke with him to learn more about his career, how the field of cancer immunology has evolved, and what he sees for the future.

Ton Schumacher at CICON in 2019.

Arthur N. Brodsky, PhD:

When your career started in the late 1980s, the concept that T cells could recognize cancer was still far from accepted. So, before you thought about exploring basic immunology in the context of cancer, you were initially focused on just the basic immunology side of the equation, looking at how T cells see regular or infected cells and their antigens?

Ton N. Schumacher, PhD:

Yeah, my work has led me to cancer neoantigens, but it started at the much more fundamental level of how antigens are presented by cells infected by viruses, and how these cells are then recognized by T cells.

My initial interest in the field revolved around wanting to understand the mechanisms that determine which pieces of viral proteins, known as antigens, are displayed on the cell surface by major histocompatibility complex (MHC) molecules. These MHC-bound antigens are what T cells—via their T cell receptors (TCRs)—interact with to determine if a cell is healthy or not.

In my PhD work with Dr. Hidde Ploegh, I developed technologies to measure which antigen fragments could bind to MHC molecules. That got me interested in an engineering approach toward immunology, where if there was an important question we couldn’t answer with existing technology, we created new tools to do so. That’s been sort of a common thread throughout my career, where we try to develop novel technology where we feel there is a need.

Arthur N. Brodsky, PhD:

What sparked your interest as far as applying this approach in the context of cancer?

Ton N. Schumacher, PhD:

When I finished my PhD, I wasn't part of the cancer immunology field, but soon became intrigued by the early evidence that T cells could recognize cancer cells in people treated with IL-2. In those who responded, I wondered, what were their T cells were seeing? This provided the rationale for me to turn my focus to cancer immunology and start developing novel technologies to push the boundaries of the field.

First, we developed technology to measure immune responses against many different potential antigens because we needed high-throughput technology to capture the breadth of cancer immunity. We piggybacked off tools created by Stanford’s Dr. Mark Davis (a fellow member of the CRI Scientific Advisory Council) and devised UV-sensitive “placeholder” peptides that enabled us to quickly load MHC molecules with different antigens of interest. That was some of the first technology to really allow for high-throughput screens for T cell reactivity.

Once we had this technology operational, we looked for T cells in melanoma patients that reacted to common melanoma antigens, and soon expanded our approach to identify all of abnormal proteins displayed by a person’s tumor, especially mutated ones referred to as neoantigens.

By sequencing an individual’s tumor and their healthy tissue, we could identify all the mutations, then predict which may produce a neoantigen that is presented by the MHC system and recognized by T cells. For each patient, we had a huge set of potential neoantigens, so we used our technology to screen whether T cells reacted against any of them. That led to a number of important observations.

In cancers with a lot of mutations and DNA damage, like melanoma or lung cancer, patients often have T cells that recognize tumor neoantigens, even without therapy, so the immune system is seeing the tumor. Later, we realized that you can use checkpoint immunotherapy, for instance, to boost that smoldering immune recognition, especially in highly mutated tumors with a lot of neoantigens.

Arthur N. Brodsky, PhD:

When did you first realize that you might be able to take advantage of these technologies not only to analyze patient immune responses, but also to create new immunotherapy strategies for them?

Ton N. Schumacher, PhD:

I don't quite remember when that first moment was, but seeing so many patients with tumor-reactive T cells made it clear that neoantigen recognition is an important ingredient. And that it might be possible to stimulate new antigen recognition, which I believed to be the next frontier.

That’s really where I see the field moving in the next five-to-ten years. Not just monitoring immune responses to predict which patients may be more responsive to checkpoint blockade, but also to be able to develop personalized immunotherapies, like cell therapies or vaccines, that enable a patient’s immune system to target their tumor’s unique neoantigens.

I should say there is early data, for instance from Dr. Steven A. Rosenberg—last year’s recipient of the Lloyd J. Old Award—that indicates that improving immune recognition of neoantigens can lead to clinical benefits, but those are at this point in time still a handful of studies. The field still needs to make significant steps for this to become of broad relevance to larger groups of patients.

Arthur N. Brodsky, PhD:

As you look ahead, what do you hope will be the fruits of your current work?

Ton N. Schumacher, PhD:

My dream—what I want to focus on in the next five, ten, fifteen years—is to figure out a way for us to understand what's being recognized without needing any experiments.

T cells target antigens with their TCRs, and the genetic sequences for those TCR chains contain all the information required to endow a T cell with a given specificity. Eventually, we should be able to search for those TCR codes in tumors, determine which TCRs are present there, and then infer what antigens are being recognized by the immune system.

That would be an enormous step because it would allow you to take a simple biopsy of a patient, understand what the immune system is or isn’t responding to, and then immediately use that to tailor your therapy. It also goes back to the more fundamental side of our research and trying to understand whether we can create technologies that lead to predictive algorithms for TCR specificity and further improve our efficiency.

Arthur N. Brodsky, PhD:

I understand you’re also looking at whether we might be able to use T cells from normal donors in order to identify TCRs that could be useful for people with cancer?

Ton N. Schumacher, PhD:

Yes. Several years ago, we found that from healthy people without cancer, we can isolate T cells that recognize certain defined neoantigens. Furthermore, we could show that this included T cell responses against neoantigens that weren’t picked up by the T cells of patients with tumors that carried these mutations . This work thereby taught us that, next to the neoantigens that are naturally recognized by the immune system, there are additional neoantigens present on tumor cells that aren't recognized by the immune system of the patients. Either those T cell responses were never induced or those T cells at some point were activated, but they died off over time. It led to the important realization that the naturally occurring repertoire of neoantigen-targeting T cells may not target all that is there. That's an additional incentive to develop novel adoptive T cell therapies to broaden the immune response towards other neoantigens.

Arthur N. Brodsky, PhD:

Might it be feasible for us to eventually create off-the-shelf TCR therapies with these healthy donor T cells? I know with current approved chimeric antigen receptor (CAR) T cell therapies, they have to be made anew from and for each patient.

Ton N. Schumacher, PhD:

In the long run, the T cell field may develop in reverse of the current CAR T cell therapy approaches, where the receptor (and antigen) is shared between patients, but the cell is different because they’re made with each new patient’s T cells. Issues can arise though if a patient’s T cells aren’t up to the task.

With TCR therapy, we may move to a setting in which we identify the TCRs necessary to target the tumors of individual patients, to allow recognition of the large fraction of neoantigens that are derived from unique mutations. Then, once we have the targets, we use the appropriate TCRs to redirect a donor T cell source against those targets. Once you move to this shared resource of cells, you can further engineer those cells and endow them with additional abilities. We are moving to Cell Therapy 2.0, where the classical output signals of T cells are only part of the equation. Perhaps we could also make them secrete antibodies that block immune checkpoints or produce other molecules that foster a more inflammatory tumor microenvironment (TME).

One of the miracles of cancer immunotherapy is still that, while we do see resistance occur with some frequency, if you compare it to targeted therapies for the same tumor types, resistance after immunotherapy responses is relatively uncommon. To further improve durability of responses for cancer immunotherapy, we may want to boost those properties, and we may want to use T cells not only to directly kill cells but to alter the TME to our advantage.

And all this progress, where we are today, is really a testament to the Cancer Research Institute. CRI stands out as the organization that supported the cancer immunology field in its rough years, before it was a fashionable branch of science. Personally, I am one of the people who was inspired by the early work of the CRI founders, showing that actually it was possible to mobilize the immune system to attack cancer. And that led me and many others to explore how we can use our brainpower to further understand what is happening in those patients, so we can make these approaches beneficial for more patients.

By the same token, cancer immunotherapy is really a poster child of why we should invest in fundamental research. When people started this effort, where it would lead was still very much unknown. As a personal experience, within my institutes, when we started this effort many people felt that immunology was an interesting branch of science but probably irrelevant to cancer treatment for the large majority of patients. The biggest change I have seen over the past decades is the enthusiasm that is now broadly present throughout our and other organizations, where people realize that cancer immunology has had a major impact on the lives of patients.