Cancer Immunotherapy Research: No More Nonresponders

Introduced in 2011, immunotherapy transformed the treatment of many types of cancer by activating a patient’s own immune system to attack cancer cells. Immune checkpoint inhibitor drugs, for example, used in immune checkpoint blockade therapy (a.k.a. checkpoint blockade immunotherapy) can boost a patient’s immune response by prompting their T cells to seek out and destroy cancer cells. When immunotherapy works, it’s like a miracle. Unfortunately, less than half of patients receiving immunotherapy actually improve (response rates vary widely depending on cancer and treatment types), and the improvement may be only temporary. Scientists are trying to understand the bases for these results, and whether immunotherapies can be combined with other treatments for greater success. This article looks at recent research into why only some patients respond to immunotherapy, and clues to making immunotherapy more effective for more people.

Identifying who will respond to immunotherapy

A heart-wrenching weakness of checkpoint inhibitor drugs is our current inability to predict who will benefit from them—by the time the course of therapy is complete, there may not be enough time to choose a different therapy (in the case of fatal cancers). Thus, predicting responses to immunotherapy, or defining good candidates for particular treatments, is an active research question—what makes “responders” different from “nonresponders"?

High-resolution spatial biology is a newcomer to this search for an answer. In a collaboration between Weill Cornell Medicine, NewYork-Presbyterian, the New York Genome Center, and 10x Genomics, researchers used a method called spatial protein and transcriptome sequencing (SPOTS), for high-throughput simultaneous spatial transcriptomics and protein profiling.¹ The high-resolution spatial information of protein expression, combined with measurements of gene expression, allows a detailed glimpse into cell types and activities within tissues.

Using this method, the researchers found that macrophages within mouse breast tumor tissue seem to exist in two distinct states—either fighting or protecting the tumor—at different tumor areas near different cell types. They suggest that the tumor microenvironments may play a role in whether patients respond to immunotherapy.

Another recent study from Washington University suggests that nonresponders may be lacking in CD5+ dendritic cells.² CD5+ dendritic cells are immune cells that work to activate and direct T cells in their fight against cancer, and are associated with responding to checkpoint blockade immunotherapy. Previous research from this group showed that people with cancer lived longer if their tumors contained more CD5+ dendritic cells, and that mice lacking the CD5 protein on dendritic cells didn’t respond well to immunotherapy.

Thus, a test based on CD5+ cell number or activity might be a useful predictor for response to immunotherapy. Furthermore, the researchers suggest the interesting possibility that boosting the number or activity of CD5+ dendritic cells might enable more patients to respond to immunotherapy. For example, the group found that interleukin-6 can increase the number of CD5+ dendritic cells; this may be a way to increase the efficacy and response rates of future immunotherapy treatments.

More effective and convenient immunotherapies

Much research is underway to increase the effectiveness of immune checkpoint blockade therapy. An interesting new avenue involves the use of extracellular vesicles, or exosomes—membranous spheres about 100 nm in diameter—to deliver molecular messages between cells or tissues throughout the body. In cancer, tumor cells can send out exosomes to switch off an immune response, but immune cells can likewise send out exosomes activating the immune system.

Soon, new cancer treatments may also use engineered exosomes, as recently shown to improve the effectiveness of immunotherapy by a research group at the Karolinska Institute.³ Using a mouse model of cancer initially resistant to checkpoint inhibitor therapy, the researchers found that exosomes made tumors sensitive to checkpoint inhibitor drugs, which then started to work and fight off the cancer.

The exosomes were isolated from the mice, and engineered to contain molecules known to stimulate T cells and natural killer cells of the immune system. In the future, they hope to generate therapeutic exosomes from cell lines, then store and use as needed. The therapeutic potential of exosomes is great, as they don’t trigger self-immunologic response, are easy to manufacture and freeze, and can be spiked with molecules that show therapeutic promise.

How T cells see tumor cells

Research into the cancer-fighting activities of T cells is shedding light on how interactions between the immune system and cancer affect, and are affected by, immunotherapy. A new study from UCLA and PACT Pharma suggests that the immune systems of nonresponders do, in fact, respond to immunotherapy, but their T cells “see” tumor cells differently.⁴ The researchers studied the immune responses of patients with metastatic melanoma who were receiving immunotherapy treatment with the anti-PD-1 checkpoint inhibitor drug. They isolated mutation-reactive T cells from patient samples, then used gene editing to express receptors from those cells in specially engineered tumor-specific T cells. The latter were subsequently expanded to characterize the patient’s immune responses.

The researchers found that responders had a diverse, polyclonal group of T cells that expanded to recognize mutations in tumor cells during immunotherapy. In contrast, nonresponders had a monoclonal group of T cells that could recognize tumor cells (albeit not sufficiently to respond to treatment), but had not expanded in diversity over the course of immunotherapy. The results suggest that it may be possible to strengthen the immune responses of cancer patients—even in apparent nonresponders.

Recent studies are beginning to explain why some cancer patients don’t respond to immunotherapy, which may help to steer patients and their physicians toward treatments more likely to succeed. The tantalizing notion of potentially transforming nonresponders into responders by changing patient phenotypes is an exciting area of future research. Studying the interactions between cancer cells and the immune system may hold the key to unlocking successful immunotherapy for all cancer patients.

References

1. Ben-Chetrit, N., Niu, X., Swett, A.D. et al. Integration of whole transcriptome spatial profiling with protein markers. Nat Biotechnol (2023). https://doi.org/10.1038/s41587-022-01536-3

2. He M, Roussak K, Ma F, et al. CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses. Science. Feb. 17, 2023. DOI: 10.1126/science.abg2752

3. Rosanne E. Veerman, Gözde Güclüler Akpinar, Annemarijn Offens, et al. Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model Cancer Immunology Research, online 22 December 2022, doi: 10.1158/2326-6066.CIR-22-0540.

4. Puig-Saus, C., Sennino, B., Peng, S. et al. Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy. Nature, 2023 DOI: 10.1038/s41586-023-05787-1