The first therapeutic cancer vaccine, approved more than a decade ago, targeted prostate tumours. The treatment involves extracting antigen-presenting cells — a component of the immune system that tells other cells what to target — from a person’s blood, loading them with a marker found on prostate tumours, and then returning them to the patient. The idea is that other immune cells will then take note and attack the cancer.
The 2010 decision by the US Food and Drug Administration (FDA) to approve this vaccine — called sipuleucel-T — raised hopes for a surge of cancer treatments that use the body’s natural capabilities to destroy the enemy within. Immunotherapies have at least partially delivered on that promise in many types of cancer. But not in the prostate.
Part of Nature Outlook: Prostate cancer
“Prostate cancer has been a big challenge in terms of getting immunotherapies to work,” says Lawrence Fong, a cancer immunotherapist at the University of California, San Francisco. Even sipuleucel-T was not an unqualified success. It delivered a slight survival benefit, but had no effect on tumour size or symptoms1.
In the decade since sipuleucel-T’s arrival, there have been numerous trials of immunotherapies for prostate cancer, most of which have been disappointing. But researchers are not ready to give up yet. They are gaining a better understanding of why this cancer has proved so difficult to crack, and a number of approaches to harnessing the immune system in prostate cancer are showing promise in trials — including new vaccines and therapies based on engineering cells to destroy cancerous tissue. Many oncologists are convinced that better targeting of treatments to individuals, plus combinations of therapies that can pull several levers of the immune system, will finally deliver immunotherapies that provide a prolonged benefit to people with prostate cancer.
One of the great cancer-therapy success stories of the past decade has been the development of immune checkpoint inhibitors. These drugs block a switch that cancer cells press to sabotage T cells — immune cells that would otherwise seek out and kill them. The approach has worked wonders for people with skin and lung cancers, but has had a hard time in the prostate. “We’ve had multiple phase III clinical trials that have been negative,” says Fong. One checkpoint inhibitor, called pembrolizumab, was approved by the FDA in 2017 for tumours with genetic faults that prevent DNA repair, but less than 5% of men with advanced prostate cancer have such tumours — a considerably lower proportion than in some other cancers.
The failure of checkpoint inhibitors to make an impact in prostate cancer did not come as a complete surprise; there was very little preclinical evidence to suggest that they would work for prostate tumours just as they had for other cancers. Many clinical trials “were done out of practicality, because we had an approved agent,” says Doug McNeel, an oncologist at the University of Wisconsin–Madison. Sometimes checkpoint inhibitors were tested more out of hope than in expectation of success. Often, there was little understanding of why a trial had failed.
The gaps in the understanding of prostate tumours are a key obstacle to getting immunotherapy to work. “We haven’t done enough immune profiling of the prostate microenvironment in humans,” says Mark Linch, a uro-oncologist at University College London. “We’ve done a lot in mouse models, but these don’t recapitulate the most common type of prostate cancer.” Increasingly, researchers are scrutinizing biopsies taken before and after treatment, to better understand an individual’s tumour and their immune response.
Some well-known characteristics of prostate tumours seem to make them difficult targets for immunotherapy. One is that prostate cancers tend to mutate less than other cancers, and therefore present fewer targets for immune cells. “There’s just not as much fodder for T cells to recognize,” says Charles Drake, vice-president of immuno-oncology at Janssen Pharmaceutical and an oncologist at Columbia University Medical Centre in New York City.
Another is that the prostate has an unusually dialled-down immune environment. “There are not a lot of immune cells in the prostate when you do biopsies, and most of those there are not activated,” says James Gulley, an immuno-oncologist at the US National Institutes of Health (NIH) in Bethesda, Maryland. Researchers using genetic sequencing to look for immune cells in the prostate will often come away empty-handed. “If you analysed the entire tumour, you would miss the signal from T cells because there are so few,” says Julie Graff, a prostate oncologist at Oregon Health & Science University (OHSU) in Portland. This poses a problem for checkpoint inhibitors. If there is a shortage of T cells to begin with, simply switching on those that are there is unlikely to do much good.
The lack of immune cells might be due partly to the position of the prostate along the urinary tract, which is a conduit for infectious organisms. So as not to overreact to these organisms, “prostate tissue, by its very nature, has an immunosuppressive milieu,” says Fong. Add in the cancer, which secretes a chemical messenger that further dampens immunity (as well as encouraging metastasis), and you have a tricky environment for an immunotherapy to operate in. “It makes it harder to light a fire when you have wet wood,” says Gulley. “We’ve got to figure out a way to dry it out.”
Graff’s research hints at one potential approach. She and her colleagues showed that testosterone can limit the body’s response to immunotherapy — and therefore that therapy to reduce a person’s testosterone levels might boost cancer-fighting T cells2. Hormone blockers are already commonly used in people with prostate cancer — almost all prostate tumours respond to this therapy initially, before resistance develops. Combination immunotherapies might have more success than one immunotherapy alone. “Prostate cancers are like an onion: there are so many barriers to the immune system, and you must start peeling them away,” says Graff.
Therapeutic cancer vaccines in the mould of sipuleucel-T have so far been a bit of a let-down. “There have been shedloads of vaccine trials for prostate cancer,” says Nick James, a prostate-cancer researcher at the Institute of Cancer Research in London. “They’re all underwhelming.” But some researchers think there is still hope, particularly in combination with other agents. The basic idea is to use a vaccine to spark an immune response and increase the number of T cells, and a checkpoint inhibitor to degrade tumour defences against those T cells.
Sipuleucel-T did have some impact: in one study, prostate tissue samples from people who received the treatment contained three times as many activated T cells, in most cases, as did samples from people who did not receive sipuleucel-T3. “That treatment did demonstrate that we could prime an immune response,” Fong says, even if it was not enough by itself to get into the clinical end zone. Another vaccine, Prostvac (PSA-TRICOM), used a poxvirus to deliver a gene that spurred production of molecules for rousing T cells and improved targeting of prostate-specific antigen (PSA), which is made in large quantities by prostate cancer cells. However, after showing some promise, it disappointed in a phase III trial in 20194. “That was a blow to all of us,” says Drake. Gulley, who was involved in the development of the vaccine, says that although it generated an immune response, the immune cells might then have been unable to infiltrate the tumour.
In an attempt to break the blockade, Gulley’s group is trialling the use of Prostvac alongside a checkpoint inhibitor that targets a protein on T cells called PD1, which tumours use to evade the immune system. Early results from a small cohort, as yet unpublished, show a notable response in some people: two have seen their PSA levels drop by more than 90%, and one shows no evidence of disease more than five years on. “Not a home run, but an interesting early signal,” says Gulley.
Various other combinations of vaccines and checkpoint inhibitors are being trialled. For example, Linch is working with biotechnology company BioNTech, headquartered in Mainz, Germany, on a clinical trial of an mRNA vaccine for prostate cancer, in which some participants will receive both the vaccine and a checkpoint inhibitor called cemiplimab that has been approved for skin cancer. Similarly, McNeel has tried combining a vaccine that primes the immune system to respond to androgen receptors — which prostate cancer cells tend to make more of when testosterone levels are suppressed — with pembrolizumab. Other trials have combined Prostvac with ipilimumab, a monoclonal antibody that targets CTLA-4, a protein on regulatory T cells that deactivates other T cells.
Gulley’s next step, meanwhile, has been to add a third element to the mix: interleukin-15, a cytokine molecule involved in immune signalling. He hopes that it will provide an extra boost to T cells, as well as immune cells called natural killer cells. In an ongoing trial, some people are showing a strong response5, Gulley says, including two whose cancer had spread to the bone but is now undetectable on scans. His group is now devising a larger test of this triple-hit approach. As all three elements of the therapy are experimental, however, the project must clear tough regulatory hurdles.
The combination of vaccines and checkpoint inhibitors is not the only flavour of immunotherapy being pursued for prostate cancer. CAR-T therapy — involving extracting T cells from a patient, engineering them to target specific cancer cells and returning them to the individual — has electrified the oncology field because of its success against blood cancers. Despite underwhelming results against solid tumours, CAR-T cells are now being deployed in early clinical trials against prostate cancer.
Earlier this year, Naomi Haas, a prostate-cancer researcher at the University of Pennsylvania in Philadelphia, and her colleagues reported treating 13 people with CAR-T cells engineered to target prostate-specific membrane antigen (PSMA)6. PSMA is rarely found in most tissues, but is present on the outside of around 80% of prostate cancers and becomes more prevalent as the disease progresses. Three people in the trial showed a reduction in PSA levels of more than 30%, but five experienced a runaway inflammatory reaction known as cytokine release syndrome, and one of them died. A similar trial, run by the Philadelphia-based company Tmunity Therapeutics, was stopped after two people died from neurotoxic side effects. Haas’s team is considering whether the therapy can be given more safely, such as by injecting the CAR-T cells directly into the tumour rather than systemically.
Another treatment strategy that is intriguing the field is the use of bi-specific T-cell engagers (BiTE) — monoclonal antibodies with two hooks. One hook grabs T cells by a surface receptor called CD3, while the other takes hold of a protein on the outside of tumour cells, bringing the two cells together. “You just need any old T cell in the vicinity of a cancer cell and it’ll attack,” says Graff.
One BiTE currently under investigation is acapatamab (AMG 160), developed by pharmaceutical company Amgen in Thousand Oaks, California. This brings hooked T cells over to tumours by binding to PSMA. Even in people heavily pre-treated with other therapies, response rates in the phase I trial approached 33%7. “That’s pretty exciting,” says Linch, who is now running a trial that combines acapatamab with a PD1 blocker or a hormone therapy. The downside, he adds, is that again there was a significant incidence of cytokine release syndrome. Drake thinks that versions of these molecules with a lower affinity for CD3 “might have activity without stoking the bad cytokines”.
The right way to do it
For immunotherapies to deliver the greatest value, they will need to be targeted to the right people. “Prostate [cancer] is going to be an immunologically responsive disease,” says Haas. “We just need to better divide the patient populations.” This sort of personalization is already common in treatment of breast, kidney and skin cancers, but is lagging in prostate cancer.
Drake, however, thinks that it shouldn’t be necessary to limit treatments to small groups of people whose tumours fit a narrow set of criteria. “We don’t select patients for chemo for prostate cancer — it just works,” he says. “If we had an effective combination regimen with immunotherapy, we could probably help the majority of patients.”
There is growing consensus that the timing of an immunological intervention could be crucial. “Most immunotherapy approaches have been taken in patients with quite advanced disease,” says Haas. But the longer a cancer fights off a patient’s immune system, the more entrenched it can become. “In advanced tumours, there aren’t a lot of T cells,” says McNeel. “Maybe we’ve been targeting the wrong stage of the disease.” He suggests that it might be better to deploy immunotherapy immediately after surgery or radiation therapy, to prevent the disease coming back. There are also hints that radiotherapy might prime the immune system, perhaps by cracking open cancer cells and inducing an immune response.
Drake thinks that immunotherapy should be given before hormone therapy. Once patients have their testosterone levels lowered in this way, T cells make their way to the prostate gland and inflammatory cytokines are released. But what comes next is a wave of cells that suppress the immune response, says Drake, so delivering immunotherapy ahead of that could be advantageous. It could potentially even remove the need for hormone therapy altogether and avert its side effects, such as muscle loss, weight gain and fatigue. “If you can give the immunotherapy for a few months and it doesn’t work, you can always give hormone therapy then,” he says.
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Although immunotherapy might be easier to get working earlier in the course of disease, it might do more good if it could help people whose cancer has spread beyond the prostate. If prostate cancer is caught early, combinations of radiotherapy, surgery, hormone therapy and other drugs can be curative. But once the disease has metastasized, invariably to the lymph nodes or bone, options are few. “Metastatic prostate cancer remains a lethal disease,” says James.
Graff remains hopeful that immunotherapy could change this. She points to a phase II trial of a combination of the androgen-receptor-blocker enzalutamide and the checkpoint inhibitor pembrolizumab, in which 5 out of 20 participants showed an exceptional response, despite the fact that the cancer had already spread to the bone in two of them8. In her view, a successful immunotherapy for prostate cancer must be one that can also hit tumours in the bone.
Optimism over the development of prostate-cancer immunotherapy is based mainly on a small number of strong responders in clinical trials — but the sentiment is shared by many researchers. “We’re seeing little signals, like in our triplet study, that some patients can have long-term durable responses with immunotherapy,” says Gulley. Fong, too, sees glimmers of hope in the strong clinical responses seen with BiTE and CAR-T therapies, despite the unacceptable side effects. “The trials showed clinical efficacy,” he says. Drake has seen enough responses to immunotherapies to remain ebullient. “I truly believe that the right combination of agents can lead to prostate-cancer patients being cured,” he says.
Ultimately, prostate-cancer treatment is playing catch-up. “Prostate cancer is about 15 years behind some of the other cancers,” says Haas. She points out that it wasn’t until 1996 that chemotherapy was effective for prostate cancer. Questions about the tumour microenvironment and how best to target immunotherapy are well on their way to being answered for many other cancers, but still hold much mystery in prostate cancer. “We haven’t quite cracked it,” says Gulley, “but there is optimism that there will be a path forward.”