Improving Cell Therapies by Characterizing Our Immune Arsenal with CRI STAR Dr. Ning Jenny Jiang

In June 2021, Ning Jenny Jiang, PhD, of the University of Pennsylvania (UPenn), was named a Cancer Research Institute (CRI) Lloyd J. Old STAR, a program honoring the “Father of Modern Tumor Immunology” who served as CRI’s founding scientific and medical director. STARs (Scientists TAking Risks) receive $1.25 million over five years to implement their potentially transformative research ideas.

As the Peter and Geri Skirkanich Associate Professor of Innovation in UPenn’s Department of Bioengineering, Dr. Jiang seeks to characterize the incredibly diverse T cell repertoires in patients, which make up a crucial component of our immune arsenal, especially against cancer. By tackling this complex challenge, Jiang hopes to optimize our ability to design personalized cell therapies for patients, as well as improve the methods through which doctors tailor overall immunotherapy strategies to individuals.

We spoke with her recently to learn more about the research she’ll be pursuing as part of her CRI Lloyd J. Old STAR grant.

Arthur N. Brodsky, PhD: 

Hello Dr. Jiang, and congratulations on your CRI Lloyd J. Old STAR grant!

Ning Jenny Jiang, PhD: 

Thank you, Arthur. Thank you for taking the time. I’m really honored to be one of the awardees.

Arthur N. Brodsky, PhD: 

We’re happy to have you! So, against viruses, T cell responses are usually concentrated against one or two antigens, which are the markers that the immune system uses for recognition. As far as T cell responses against cancer, how are those different? And what implications does that have for our immunotherapy strategies against cancer?

Ning Jenny Jiang, PhD: 

For a lot of viruses, T cells can recognize many different antigens. But there are a few viral antigens that are recognized by almost everyone’s T cells. For cancer though, there are different categories of tumor antigens. Neoantigens are one of the types gaining a lot of attention recently. These abnormal protein fragments arise from cancer’s mutations and are emerging as a very effective way of targeting cancer by T cells. Additionally, two other really important categories of cancer antigens are cancer-associated antigens and cancer-testis antigens. Cancer-associated antigens are antigens that are not unique to cancer, but also expressed on healthy tissue, although usually at lower densities. The cancer-testis antigens are restricted to human testes and not expressed in any other healthy tissue. Fortunately, because testes have low levels of MHC—the molecules that present the antigens for T cells to recognize—the T cells will not actually attack them. But those antigens are abundantly expressed in cancer. As a consequence, both of these types of antigens, neoantigens and cancer testis antigens, are great targets for T cell immunotherapies.

Arthur N. Brodsky, PhD: 

Do we know how neoantigen-targeting T cells differ in terms of their function from the T cells that target cancer-testis antigens or cancer-associated antigens? Additionally, do the different antigen types have different effects on T cells in terms of the development of immune memory—a beneficial process we want to promote—versus immune exhaustion, where T cells become dysfunctional and ineffective against cancer?

Ning Jenny Jiang, PhD: 

There is a long history behind the study of cancer-targeting T cells. Through generations of research, we’ve discovered a lot of cancer antigens, and many of them are actually shared between patients. The differences between the three categories we just talked about—the neoantigens, the cancer-testis antigens, and the cancer-associated antigens—is that the T cells that recognize them are generated slightly differently. And that’s why the neoantigen-targeting T cells are so important, because they actually are similar to T cells that recognize viral antigens. As a result, they are believed to be more robust, better at killing cancer cells, and more likely to generate immune memory that can protect us against relapse in the long term. However, this hasn’t been comprehensively characterized and confirmed in human patients yet.

Arthur N. Brodsky, PhD:

To that end, one of the goals of your work is to optimize the technologies you’ve been developing so you can use them to detect whether cancer patients have “holes” or weak spots in their repertoire of cancer-fighting T cells. Can you talk a little bit about what you mean by holes and weak spots, and how these gaps might be addressed therapeutically?

Ning Jenny Jiang, PhD: 

In our studies of healthy individuals, who have some natural immune protection against commonly encountered viruses like the flu, we noticed that not everyone has T cells that cover all the possible antigens. There are differences in the number and types of flu-targeting T cells that each individual has. For some “exotic” antigens, like those of HIV for example, although the general population doesn’t actually have exposure to them, they should still have a very low level of minimum T cells that can offer some protection from possible future infection. So that part of our T cell arsenal acts as a safety net. But some individuals may completely lack those T cells. In those cases, as you can imagine, those people will have a hard time overcoming a future infection.

The same principles apply, in a sense, to people with cancer. Not all patients have an adequate T cell repertoire to protect them from all possible cancer antigens or all the mutations that cancer might express. In the case of cancer, if a patient lacks some cancer antigen-targeting T cells, then adoptive cell therapy may actually help them, by providing them with T cells that target their cancer. These would be their own T cells, that we enhance and equip with the right T cell receptors to target and eliminate their particular tumor.

Arthur N. Brodsky, PhD: 

The foundation of your work focuses on just trying to figure out the fundamental mechanisms of T cells recognizing these different antigens, and then how that influences their behavior, but obviously, the end goal is to help patients. Given that every patient’s cancer is unique, and as a result, so would the necessary cancer-targeting T cells, analyzing all these factors in every individual patient seems like it would be very challenging to do quickly enough so that it would make a difference for a patient in the hospital.

How might your work help impact clinical care by enabling doctors to better tailor therapies to individual patients in a timely manner?

Ning Jenny Jiang, PhD: 

Right. Some cancer antigens—usually derived from the “driver” genes that promote cancerous behavior—are shared among different patients. If we discover T cells that recognize those shared driver mutations, then off-the-shelf versions of those T cells can be made in advance, so they’ll be ready for patients who have that mutation as soon as they’re needed.

But in general, like you said, most patients’ tumor antigens are unique, and that makes it very challenging to do a case-by-case study. That’s why we’re analyzing hundreds of different antigens in parallel and in a high throughput manner, looking at all the individual T cells. Overall, we hope that our technology fills this technical gap, so that we can speed up the processes involved in developing personalized T cell therapies.

Arthur N. Brodsky, PhD: 

Earlier, you said that once you’ve figured out what antigens a patient’s cancer expresses, you might be able to design T cells to target that specific antigen. Is it possible that you also might target these cancer antigens with vaccines too, once you know what antigens you’re going after?

Additionally, could your technologies help provide insight to doctors and suggest which treatments, such as checkpoint immunotherapy, might be more likely work for a given patient?

Ning Jenny Jiang, PhD: 

Exactly. As we do a comprehensive survey of all the different surface molecules as well as the gene expression of individual cells, we can pinpoint the exact exhaustion status of each individual patient’s T cells, and then can give more tailored therapy suggestions.

This also ties back to the T cell repertoire hole. So many of the cancer patients who receive checkpoint immunotherapy do not respond to it. That leads us to ask if their T cell repertoires are complete and functional to begin with? If we find there are holes, then we can patch them by borrowing T cell receptors from other individuals and equipping their T cells with the appropriate receptors.

Arthur N. Brodsky, PhD: 

As you mentioned, this is not an easy undertaking, and there are a lot of challenges associated with it. How is this CRI STAR funding helping you to tackle this high-risk, high-reward endeavor?

Ning Jenny Jiang, PhD: 

I’m very grateful for the CRI support via this unconventional award mechanism, which seeks to support really risky, but potentially paradigm-changing proposals. This kind of work might not be funded by the National Institutes of Health or other traditional mechanisms. So, CRI gives us an opportunity to carry out this project that we hope will enable us to find a better and faster way to achieve patient-specific cancer immunotherapy strategies.

Arthur N. Brodsky, PhD: 

Overall, what do you hope to accomplish over the next five years with CRI’s support? And what are your hopes for how the field might look in five years?

Ning Jenny Jiang, PhD: 

Right now, our technology is only available for CD8⁺ killer T cells. As you probably know, there are other types of immune cells that are heavily participating in immune responses, for example, B cells and CD4⁺helper T cells. We’re eager to expand our toolbox to cover all of those cells and really achieve a holistic analysis of the tumor microenvironment, because we believe that they come to tumor for a reason. We also need to understand why they’re there. In the future, hopefully we will be able to pay more attention to everything that’s happening in the tumor microenvironment, and how the T cells and B cells work together. Then, we could design more effective therapeutic approaches for patients depending on the composition and immune system of their individual tumors.