Checkpoint Immunotherapy

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Improving Cell Therapies by Characterizing Our Immune Arsenal

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.

Against viruses (SARS, COVID), 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?

For cancer 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. 

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?

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 above —the neoantigens, the cancer-testis antigens, and the cancer-associated antigens—is that the T cells that recognize them are generated slightly differently.

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.

To that end, the goal is to optimize the technologies to use them to detect whether cancer patients have “holes” or weak spots in their repertoire of cancer-fighting T cells, and how these gaps might be addressed therapeutically?

Recent studies of healthy individuals, who have some natural immune protection against commonly encountered viruses like the flu, it has been 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 tumour.

The foundation of recent work focuses on trying to figure out the fundamental mechanisms of T cells recognizing these different antigens, and then how that influences their behaviour, 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, analysing 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 hospital.

The key is to find a way via clinical care, to enable doctors to better tailor therapies to individual patients in a timely manner?

Some cancer antigens—usually derived from the “driver” genes that promote cancerous behaviour—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.

In general, most patients’ tumour antigens are unique, and that makes it very challenging to do a case-by-case study. By analysing 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.

Once we’ve figured out what antigens a patient’s cancer expresses, we might be able to design T cells to target that specific antigen. Is it possible that we also might target these cancer antigens with vaccines too, once we know what antigens to go after? Additionally, technologies could help provide insight to doctors and suggest which treatments, such as checkpoint immunotherapy, might be more likely work for a given patient?

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.

This is not an easy undertaking, there are a lot of challenges associated with it. This kind of work might not be funded by the National Institutes of Health or other traditional mechanisms. So, independent funding is the only opportunity to carry out this type of project that we hope will enable us to find a better and faster way to achieve patient-specific cancer immunotherapy strategies.

Ning Jenny Jiang, Ph.D.: – Right now, our technology is only available for CD8⁺ killer T cells. 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 tumour microenvironment, because we believe that they come to tumour 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 tumour 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 tumour’s.

Thanks for Reading

Peace