From the Bench to the Clinic Part 1: Martin McIntosh, Ph.D., Introduces His Lab's Immunotherapy Research

Edited by Nadia Jaber and Jessica Mazerik

The field of immunotherapy is rapidly advancing and genomics techniques are being incorporated to add a “precision” approach. OCG spoke with two CTD2 investigators from the Fred Hutchinson Cancer Research Center (FHCRC) about new advances in immunotherapy. For the first article of this two-part series, we interviewed Martin McIntosh, Ph.D., member of the Fred Hutchinson Translational Research program and previously Program Head in Computational Biology at FHCRC/University of Washington Comprehensive Cancer Center. He gives his perspective of immunotherapy approaches and describes his laboratory’s translational research efforts.

Can you describe the different types of immunotherapy approaches?

In broad terms, there are several classes of immunotherapies. All tumors are thought to adopt strategies that interfere with normal T cell function. One class of immunotherapy tries to overcome obstacles to T cell efficacy that are present in the tumor. These treatments are predicated on the notion that an effective anti-cancer immune response is already present within a patient. Agents that block T cell inhibitory pathways, including anti-PDL1 (programmed death ligand 1) and anti-PD1 (programmed cell death protein 1) are examples of this class. Unlike conventional therapies, the agents are not necessarily directed to the tumor cells; instead, they block signals within the tumor microenvironment that inhibit T cell function.

Adoptive cellular therapies are another class of immunotherapy. For these therapies, a patient’s T cells are removed from circulation and expanded ex vivo in the presence of a tumor antigen, then re-infused into the patient. This allows any existing anti-tumor T cells to divide, amplify, and affinity mature*. The result is a super-charged population of T cells that are ready to attack any cells that express the antigen. Adoptive therapies may have been the first and may possibly still be the only truly personalized cancer therapy; T cell expansion can be performed in the presence of tumor material obtained from a patient’s biopsy, or by using a synthetic antigen identified by genomic or proteomic interrogation of a biopsy sample.

A third class combines adoptive cellular therapy with cellular engineering to target cancer cells that express a shared tumor antigen**. During the ex vivo expansion step of adoptive cellular therapy, a patients’ T cell receptors (TCR) are modified to express a high-affinity T cell receptor or Chimeric Antigen Receptors (CARs) that are specific to a shared tumor antigen. For CAR T cells, the TCR is replaced with a modified B cell receptor that recognizes a tumor-specific antigen. The CARs and TCRs used in these approaches can be obtained from unrelated individuals, including healthy individuals, whose immune cells have been observed in the laboratory to recognize a tumor. Because they recognize shared antigens, a CAR identified for one patient can be used to engineer CAR T cells for unrelated patients. 

*Editor’s Note: Affinity maturation is accomplished by starting with T cells that harbor a receptor that recognizes a target antigen to some degree and systematically mutating it to increase avidity.

**Editor’s Note: A shared tumor antigen is one that is present in a significant number of patients’ tumors.

How does your laboratory research fit into these immunotherapy approaches?

Our role is to identify target antigens that can be used for adoptive T cell therapy approaches with or without engineered T cells. Most tumors have antigens that are the products of mutated genes, which are identifiable through conventional exome sequencing. To be practical for therapy, the mutated gene must give rise to a product that is processed by the proteasome, presented on the surface of cancer cells, and recognized by T cells. Most mutated genes do not meet these criteria.  Also, mutations are rarely shared between patients, so they are useful only for precision approaches and are not yet viable candidates for engineered therapies. This means each patient would require a unique T cell immunotherapy.  We are testing approaches to rapidly identify large numbers of polypeptides that are highly immunogenic and expected to be shared in most tumors. The ultimate goal is to find an immunogenic polypeptide that is shared by multiple tumor types so that a single therapy would be efficient for all, or many, people.

Which tumor types are you studying?

We have done most of our work in ovarian tumors and cell lines, but we also reproduce all experiments using pancreatic and lung tumors and cell lines to ensure that what we are seeing is not idiosyncratic to a single cancer type. We also conduct extensive mining of public data sources that profile normal tissues, specifically the Genotype-Tissue Expression (GTEx) project, to ensure that we are identifying tumor-specific variants.

How can immunotherapy approaches be tailored to each patient?

Antigens that are expressed uniquely in each patient’s tumor can be used to generate personalized adoptive cellular therapies. Additionally, each patient is thought to have different combinations of immune-suppressive factors that inhibit T cell function, and these same factors can also inhibit engineered T cells. Identifying immune-suppressive factors in tumors is a necessary part of our effort, but we rely heavily on our collaborators within the Fred Hutch who are doing the leading work here. We can identify factors that may be at play, but the immune system is complex and dynamic. Predicting the outcome of circumventing any apparent barrier has not been solved at this time. In principle, with the large and growing number of FDA-approved immune-modulatory agents, one can imagine using a unique combination of drugs to steer each patient’s tumor away from its immune-suppressive state.

What do you perceive as the key advantages of immunotherapy?

One is that T cells are self-renewing and non-limiting. Thus, once tumor-specific T cells are established they can survive for years and fight off the tumor if it recurs. From a personal perspective, what drew me to this area is the time frame for making an impact. For conventional therapy, the time frame from identifying a target to testing in humans is long and reliant on factors entirely out of the control of a researcher, such as investment by pharmaceutical companies. In contrast, our institute and our collaborators’ institute, the University of Texas MD Anderson Cancer Center, have in-house facilities to develop adoptive T cell therapies. These are most often used in patients who have failed all other therapies, so time is of the essence. For example, we are piloting work with a collaborator at MD Anderson (Dr. Cassian Yee) to determine whether we can rapidly and consistently identify immunogenic polypeptides and use them for immunotherapies. We will first test these antigens in human immune cells in vivo, of course, and if the results are promising, Dr. Yee could use the antigens we identify to treat very ill patients. It is very motivating and rewarding to know that what we do today could possibly impact patient care in a time frame that one can see.

What are the shortcomings of immunotherapy approaches?

I see two shortcomings that I think can be overcome. One is that tumors evolve with treatment and they can simply adopt different mechanisms to evade the immune system. The other is that T cells are self-renewing and non-limiting; I noted this as an advantage, but it is also a disadvantage because if the T cells used for therapy recognize healthy cells, they can attack and damage healthy organs. Mechanisms to cope with these obstacles are currently being tested.

How has being involved in the CTD2 Network affected your lab’s experimental scope and design?

The CTD2 Network defined “Tiers” to describe the extent to which CTD2-generated results have been validated. The Tiers start with in vitro observations and advance to in vivo confirmation. We changed our approach to follow the principle of the Tiers more closely.

Other influential aspects of CTD2 are the diverse research focuses of the Network and the collaborations that merge these different areas of research. Many CTD2 researchers use functional biology approaches to identify critical molecules or pathways in cancer cells and therapeutic agents to target them. In developing these as potential therapies, one consideration is, how can we deliver those agents specifically to cancer cells? What I recognized is that the part of our CAR T cell identification efforts could be used to assist with the problem of drug delivery, which may often require targeting a receptor on the surface of cancer cells to help internalize the drug. To do this, we have made our approach more general by focusing on more than just T cell targets and considering all surface antigens. I think there are many valuable resources generated by CTD2, like data and methods, but the real value of the Network lies in the less tangible aspects, like shared ideas and collaborations. I have learned a great deal from the Network. The group meetings are dynamic. I leave every group meeting with new ideas that we incorporate into our effort. I think members from other Centers feel the same way.

Stay tuned for the next installment of “From the bench to the clinic part II” in our eNewsletter.

To learn more about Dr. McIntosh’s research, visit the Fred Hutchinson Cancer Research Center (2) CTD2 Center description. Visit the National Cancer Institute’s website to read more about immunotherapy.

Last updated: April 24, 2022