A better understanding of clinical outcomes, tumour dynamics and immune system interactions could lead to better outcomes.

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CAR-T-cell therapies have delivered transformative benefits for many cancer patients, but some recipients respond better than others.Credit: Thom Leach/Science Photo Library/Getty

Crystal Mackall has seen the transformative impact of cellular therapies in paediatric oncology. She was among the first to show that engineered immune cells can be safely deployed to combat cancer in children, initially targeting blood malignancies and later deadly brainstem tumours.

In some cases, “the long-term durability of the clinical benefit is unbelievable,” says Mackall, founding director of the Stanford Center for Cancer Cell Therapy in California. And yet, not everyone who receives these chimeric antigen receptor (CAR) T cell therapies experiences the same results.

This variability led Mackall to ask: Why do some patients respond better than others? “This is the question that needs to be answered,” she remarked to a gathering of scientists and clinicians at Cancer Immunotherapy: From Bench to Bedside and Back, a Nature Conference held in partnership with the Dana-Farber Cancer Institute (DFCI) in Boston, Massachusetts.

The issue of patchy responsiveness is not limited to engineered cell therapies. From cancer vaccines and antibody therapies to immune-modulating agents and tumour-attacking viruses, the field of cancer immunotherapy is replete with examples of remarkable successes — but also failures.

The cancer research community now faces the challenge of unravelling the underlying mechanisms responsible for varied responses to immunotherapy.

By profiling and characterizing immune and tumour cell states, along with their interactions across different spatial and temporal scales, researchers are deepening their understanding of what drives immunotherapy success and resistance. They are also devising new methods to engineer cells, proteins, RNA, and other molecules for improved therapeutic efficacy.

Collectively, this knowledge is leading to the creation of more personalized and effective treatment strategies for all manner of blood cancers and solid tumours.

“We are witnessing this amazing convergence of new technological innovations that enable us to delve deeply into the patient experience and gain insights directly from tumour samples,” said Catherine Wu, an oncologist and cancer vaccine researcher, who co-organized the conference with several DFCI colleagues and Nature Portfolio editors.

Those insights should then translate into testable hypotheses that can be rigorously evaluated in the laboratory before clinical implementation. According to Wu, this iterative process can then be repeated as needed until it yields improved outcomes — and potentially even cures — at the cancer clinic.

“Ultimately,” she notes, “it is the basic research discoveries that will propel us toward new therapeutic avenues.”

Cellular scrutiny

Many basic scientific discoveries discussed at the conference centred around the mechanisms by which cancer-killing T cells operate and factors that help explain why these cells respond or not to immunotherapies to rein in cancer growth.

Ageing presents one such impediment. Age-related signals contained within the tumour microenvironment (TME) can drive these cytotoxic T cells into a dysfunctional state.1 “One that is molecularly distinct from the ‘exhaustion’ phenotype that often underpins the diminished functionality of these cells,” says Alex Chen, a cancer immunologist at the Massachusetts General Hospital in Boston.

But tumour-reactive T cells are not the only elements involved in anti-cancer immunity, notes Michael Angelo, a pathologist and computational biologist at Stanford University School of Medicine in California, who uses multi-omics approaches to analyse TMEs at different spatial scales. “Tumours don’t exist within a vacuum,” he says. “They’re part of this complex ecosystem,” rich with a multitude of cell types and metabolites that collectively both support and hinder T cells from effectively targeting and destroying cancer cells.

Interactions between these different cell types are critical, too. Andrea Schietinger, a tumour immunologist at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, has shown how a single dendritic cell must engage with both tumour-specific CD4+ and CD8+ T cells simultaneously to form ‘triads’ that facilitate the immunotherapy-mediated destruction of cancers.2 “These triads are the key for target elimination in tumours,” she says.

Notably, not all tumour cells affect the immune system equally. Quiescent cancer cells, which are disseminated and remain dormant before potentially causing tumour recurrence, possess unique immune evasion strategies, says DFCI cancer immunologist, Judith Agudo. These evasive cells are thought to be a driver of resistance in people who don’t respond well to immunotherapy, and Agudo is working to identify potential therapeutic vulnerabilities.

Change for the better

Assembling a complete picture of the TME is challenging due to its complexity, diverse cell populations and dynamic interactions, complicating both analysis and treatment. Advanced machine learning techniques such as those developed by Elham Azizi, a computational biologist at Columbia University in New York City, are streamlining the process of dissecting the cellular identities and molecular circuits within tumours.

With tools that track how cancers and the immune cells interacting with it evolve in space and time, Azizi and her colleagues have begun uncovering new cellular and molecular mechanisms underlying patient responsiveness to immunotherapies. “The methods are broadly applicable,” Azizi says, explaining that her machine-learning algorithms, which are freely available to the scientific community, empower researchers “to model the dynamics of the tumour microenvironment and how it changes during immunotherapy.

”Those insights could prove valuable in the design and development of next-generation T cell therapies, particularly against solid tumours that have historically been resistant to this anti-cancer approach.

Mackall, in her keynote presentation, discussed efforts to advance a novel CAR T cell therapy for children and young adults afflicted by diffuse midline gliomas, deadly cancers of the central nervous system that are notoriously difficult to manage due to their aggressive nature and challenging location.

In early trials of this therapy, a notable success story emerged involving a 17-year-old with an inoperable brainstem tumour. After treatment, his cancer fully vanished, and the teenager has remained in remission for three years. This remarkable recovery allowed the young man to progress from wheelchair dependence to walking and running freely. Previously confined to his home and requiring constant care, he is now attending college and living independently.

This “dramatic response” bolsters Mackall’s belief that innovative CAR T cell designs have the potential to significantly impact solid tumours. Yet, this teenager remains something of an exception. While many patients have seen benefits, the cancer typically recurs, and few trial participants have survived long-term.

So, why doesn’t everyone experience the same favourable outcome? “We must delve into the biological mechanisms and patient-specific factors that influence the efficacy of these engineered cell therapies,” Mackall says.

CAR talk

One potential explanation is the gut microbiome. In a cohort of patients with B-cell leukaemias and lymphomas, Stanford haematologist, Melody Smith, discovered a link between certain types of intestinal bacteria and clinical outcomes following treatment with CD19-directed CAR T cell therapies. She also found that exposure to certain antibiotics was associated with worse survival rates and increased neurological toxicities.

“These clinical cohorts have been insightful, yet preclinical studies are needed to evaluate the regulatory mechanisms,” says Smith.

Such research could eventually lead to microbe-based interventions that, when given alongside CAR T cells, improve response rates to the cellular immunotherapy. But another strategy to boost efficacy involves refining the CAR constructs themselves to enhance performance. “The way we’ve designed CARs can be changed,” says Robbie Majzner, a paediatric oncologist at DFCI.

At the conference, Majzner showed several design elements that his lab is exploring. For example, ‘logic-gated’ CARs that only activate upon binding to two specific target antigens — a measure intended to enhance specificity and minimize on-target, off-tumour toxicity.4 His lab is also looking at methods to increase CAR sensitivity when antigen density on cancer cells is low, while other researchers are exploring ways to create ‘armoured’ CAR T cells that aggressively target and destroy tumour cells.

Misty Jenkins, a cancer immunologist at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, acknowledged the complexity of augmenting CARs in safe and effective ways. Jenkins has been searching for novel antigen targets in paediatric brain tumours. Her goal is to consolidate these targets into a single CAR T cell, enhancing the potential to engage all pertinent cancer cells and reduce the likelihood of any escaping immune detection. But more exploration is needed here. “I think we’ve barely scratched the surface,” she says.

Expanded horizons

A major limitation of most CAR T cell therapies in development is their need for customization. Tailoring treatments to each patient slows down the manufacturing process, increases costs and thereby limits availability.

One solution to this challenge is a special population of immune cells known as invariant natural killer T (NKT) cells. Unlike traditional T cells, NKT cells do not risk attacking healthy tissues in the recipient’s body, but they can be equipped with CAR constructs to effectively target and destroy tumour cells.

Tumour immunologist, Lili Yang, from the University of California, Los Angeles, and her colleagues have developed a protocol5 for making thousands of doses of NKT cells from a single cord-blood donor (taken from the umbilical cord or placenta). This technological advance paves the way for a new type of universal cell immunotherapy that Yang’s team plan to evaluate in people with multiple myeloma.

Another approach uses T-cell receptors (TCRs) rather than CARs to engage with cancer antigens, providing a wider array of targets — including in commonly mutated driver genes such as NRAS — and the potential to be adapted for a broad patient population. Christopher Klebanoff, a cellular therapist at MSKCC, described how one kind of TCR that his team identified can recognize multiple mutated forms of NRAS, a finding that could enable ‘off-the-shelf’ cellular therapy against a broad swathe of NRAS-altered tumours.

Such strategies remain years away from clinical implementation. However, other cancer therapies in widespread use today, such as stem cell transplantation and immune checkpoint inhibitors, could be more effectively deployed if informed by the right kind of research.

Trial data discussed by Christian Blank, an oncologist at the Netherlands Cancer Institute in Amsterdam, highlighted the advantages of administering checkpoint inhibitors before and after surgery to patients with advanced but still-operable melanoma, rather than solely post-surgery, which is the current standard practice. Beyond timing of inhibitors, much research in this realm is looking into novel targets.

Agenus Bio in Lexington, Massachusetts, has developed botensilimab, an Fc-enhanced antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4). This drug aims to achieve better immune activation and stronger tumour destruction compared to its predecessors. Steven O’Day, Agenus Bio’s Chief Medical Officer highlighted botensilimab’s ability to more efficiently eliminate regulatory T cells and promote priming of cancer-fighting T cells. Botensilimab, together with a PD-1 antibody, showed responses in microsatellite stable (MSS) colorectal cancer, a subtype that does not respond to first generation immune checkpoint blockers.

Ira Mellman, vice president of cancer immunology at Genentech in South San Francisco, California, also presented data that helps explain why blockade of the checkpoint molecule TIGIT, alongside inhibition of PD-1, continues to show promising results in mouse models and human patients alike. By facilitating co-stimulatory signaling — via molecules expressed on antigen-presenting cells that provide an extra boost to T cells — the dual blockade seems to prevent those cells from entering a dysfunctional, exhausted state.

“Co-stimulation plays the role in controlling not only clinical responses, but also the overall trajectory of T cells under chronic tumour antigen exposure conditions,” Mellman says.

Shot through with optimism

Cancer vaccines, once a distant goal in oncology, are beginning to fulfill their transformative promise, sparking new hope in the battle against multiple cancer types.

Olja Finn, a cancer vaccine researcher from the University of Pittsburgh Medical Center in Pennsylvania, has dedicated her career to developing a peptide vaccine targeting MUC1, a protein excessively produced by numerous tumour types. Despite previous setbacks, by refocusing the vaccine’s use for preventive measures in people with precancerous conditions rather than as a treatment, she is now witnessing encouraging success.

“You don’t have to wait for the tumour to develop,” Finn says. “We can vaccinate in the pre-malignant setting.

”Other groups are making vaccines work against established cancer by developing highly personalized products containing bespoke antigens, each selected based on mutations found in individual tumours.

These vaccines are typically administered in conjunction with checkpoint inhibitors, a combination that alters the TME in distinct and complementary ways, according to Sunita Keshari, a tumour immunologist at the University of Texas MD Anderson Cancer Center, Houston, leading to synergistic effects that enhance the overall efficacy of the treatment.

Researchers at the forefront of cancer immunotherapy are gaining valuable insights and fostering collaborative relationships that could prove vital for pushing the boundaries of what is achievable for patients. With increased data sharing and integration, the journey from bench to bedside and back won’t just be a round trip. It’ll be a guided tour, with translational discoveries providing the roadmap.