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Where are the prostate cancer immunotherapies?

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Immunotherapy for treating cancer has been one of the most exciting medical breakthroughs in the past decade. Drugs such as checkpoint inhibitors have greatly improved survival rates for a number of cancers. So where are the immunotherapies for prostate cancer?

This week’s research blog summarises a new review article that describes the past and future trials testing prostate cancer immunotherapies. The article focuses on therapies for the late stage of advanced prostate cancer, called metastatic castration-resistant prostate cancer. Men with this stage have tumours that have spread around their body, which are growing despite hormone therapy.

Different types of immunotherapy

The immune system consists of a variety of cells and proteins that recognise foreign pathogens (usually viruses, bacteria and fungal infections). These invading organisms are removed from the body via numerous different mechanisms, collectively called immune responses. The immune system is also capable of recognising and destroying some cancer cells. But this is more difficult, as the cancer cells often look like normal cells to our immune system. Most cancers are able to grow despite the immune system’s efforts to stop them.

Immunotherapy for cancer uses the body’s own immune system to kill cancer cells. This can be done by two different mechanisms:

  1. Stimulating new immune responses

Therapeutic vaccines and Car-Ts are therapies that create new immune responses to fight prostate cancer. Sipuleucel-T (Provenge) is a cell-based immunotherapy that also creates a new immune response to prostate cancer. Car-T therapies were not covered by this review paper, but the research blog will update on these experimental prostate cancer treatments in the near future.

  1. Reactivating immune responses that have been blocked by the cancer

Immune responses are tightly controlled by the human body. This level of control is important for reducing unwanted immune responses that cause damage, such as allergic reactions. Cancer cells are capable of hijacking the normal cells that surround them, changing their behaviour. Some cancer cells protect themselves by inhibiting immune responses against them. They do this by tapping into the body’s normal mechanisms for inhibiting immune responses, causing a ramp-up of the immune inhibition process.

Checkpoint inhibitors are drugs that reduce specific immune responses that the tumour cells switch on. These drugs work by switching the immune response back on, allowing it to fight against the cancer as it should be doing. Checkpoint inhibitor drugs such as pembrolizumab (Keytruda), nivolumab (Opdivo) and ipilimumab (Yervoy) have greatly improved survival rates from a number of cancers.

Prostate cancer immunotherapy

Laboratory research, animal experiments and clinical trials have been undertaken for many years to create immunotherapies for prostate cancer. There has been some success, but many failures. Writing in the journal Current Urology Updates, a team led by Dr Melissa Reimers from the Washington University School of Medicine, St Louis, USA, gave a detailed update on the latest research on immunotherapies for prostate cancer.

  • Sipuleucel-T

Sipuleucel-T (Provenge) is a cell-based prostate cancer immunotherapy available in the USA. This treatment involves removing a sample of immune cells from a patient, modifying them in the laboratory, then delivering them back into the patient in a series of treatments. It is approved by the American FDA for treatment of men with metastatic castration-resistant prostate cancer. Unfortunately, there is a massive price charged for the treatment in the USA, over $100,000, making its use uncommon. Sipuleucel-T is not approved by the TGA for use in Australia.

Clinical trials showed that Sipuleucel-T led to an increase in average survival time of 4.1 months. However, while survival time was increased, there was no evidence of a reduction in PSA levels or slowing of the disease progression. Since this treatment started in the USA, a number of other studies have tried to improve it with modifications. Adding radiotherapy did not make it more effective. Unfortunately, using it at an earlier stage of prostate cancer did not help either. However, there are some interesting results showing that a small subset of men had quite good results from Sipuleucel-T. African American men were more likely to be in this group. Further research is aimed at better identifying men who are likely to do well on Sipuleucel-T.

  • GVAX

GVAX is a therapeutic vaccine – a vaccine used as a treatment, not to prevent prostate cancer. Small pilot trials indicated that GVAX might slow the rising PSA of men with metastatic prostate cancer. Unfortunately, two phase 3 randomised controlled trials did not have positive results. One of these showed that combining GVAX with chemotherapy led to an increase in mortality rates. GVAX is therefore no longer being developed for prostate cancer.

  • PROSTVAC

PROSTVAC is another therapeutic vaccine for prostate cancer. This vaccine attempts to raise an immune response to the PSA molecule and other targets. A phase 2 trial showed promising results. This double-blinded, randomised, placebo-controlled trial showed that PROSTVAC improved the survival times of men with metastatic castration resistant prostate cancer. Men having the vaccine lived for almost 10 months longer than men who had the placebo. But curiously, there was no detectable effect on disease progression, despite the longer lifespan. Unfortunately, a large phase 3 trial testing PROSTVAC did not see a repeat of these earlier results – there was no improvement in survival times. It’s not known why the smaller trial had good results but the larger trial did not.

  • Checkpoint inhibitors

Ipilimumab (Yervoy) has been tested in a large, phase 3 randomised controlled trial. The men joining this trial had metastatic castration resistant prostate cancer, with tumours in their bones. These men had already taken chemotherapy (docetaxel). Unfortunately there was no difference in survival times for men taking Ipilimumab compared to placebo. Another phase 3 trial tested this drug for men before their chemotherapy. Again, there was no difference in the average survival time for men taking the drug compared to placebo.

Although these two trials had negative results overall, there were some signs that provide hope that Ipilimumab (Yervoy) could be useful to men with prostate cancer. In the first trial, there were subsets of men who lived for much longer than others. In the second trial, the men having Ipilimumab went longer before their disease progressed, even though this didn’t affect their survival times. Researchers hold hope that they can find a group of patients who will benefit from this drug.

Pembrolizumab (Keytruda) is another checkpoint inhibitor that has seen some success in small trials. In one trial of 23 patients, 4 of them benefitted from Pembrolizumab. This drug is particularly effective for people with specific gene mutations. It is possible for some Australian prostate cancer patients to receive Pembrolizumab (Keytruda). Men with castration resistant prostate cancer whose genetic tests indicate specific mutations are present, can access this drug once they have tried other treatments. These are only about 2 to 3% of men with advanced prostate cancer, and specific requirements must be met.

Ongoing research into prostate cancer immunotherapies

  • Combining checkpoint inhibitors with other therapies

There are ongoing clinical trials testing combinations of checkpoint inhibitors with other therapies. The aim of these studies is to make both therapies more effective. The Keynote-199 trial is testing whether patients will benefit from pembrolizumab added to chemotherapy (docetaxel). The Checkmate-650 trial is testing a combination of Ipilimumab (Yervoy) and Nivolumab (Opdivo). Initial results indicated benefits for some patients, particularly if they had no prior chemotherapy. There are multiple trials testing combinations of checkpoint inhibitors with Enzalutamide (Xtandi) and Abiraterone (Zytiga).

  • Optimising selection of patients for checkpoint inhibitors

Results from the first clinical trials indicated that a small proportion of men saw reasonable benefits from checkpoint inhibitors. Future trials are trying to choose specific men for treatment that will most likely benefit. Pembrolizumab (Keytruda) is known to be effective for people who have specific gene mutations. A new checkpoint inhibitor called Durvalumab is currently being tested in combination with experimental drug Olaparib. Patients were chosen for this trial based on the presence of DNA repair gene mutations. Another trial is testing a combination of Ipilimumab (Yervoy) and Nivolumab (Opdivo) for men with androgen receptor gene mutations called AR-V7.

  • Combination with cytokine therapy

Prostate cancer therapeutic vaccines have not been particularly effective in past trials. One approach to improving these treatments is to combine them with a process called cytokine therapy. Cytokines are protein messengers that are used by immune cells to communicate with each other. Cytokines can stimulate stronger immune responses. A phase 2 randomised controlled trial is testing a cytokine called IL-7 after Sipuleucel-T treatment.

  • Combining therapeutic vaccines and checkpoint inhibitors

A therapy that combines Pembrolizumab (Keytruda) with an experimental vaccine has made it to phase 1 clinical trials to test whether it can be delivered safely to patients. Another phase 1 clinical trial is testing a new DNA-based vaccine with Pembrolizumab. An ongoing clinical trial is testing PROSTVAC with Ipilimumab/Nivolumab in combination with a new DNA-based vaccine. Unfortunately, these trials are not recruiting men in Australia.

 

Summary

Australian men currently have very limited options for treatment with immunotherapies. A very small proportion of men with metastatic prostate cancer are able to access Pembrolizumab (Keytruda) if they have specific gene mutations and meet other requirements.

Sipuleucel-T (Provenge) is used by some men in the USA. Although this treatment appears to increase life by a few months, it is expensive, has side effects and requires international travel. Australian men with advanced prostate cancer who are interested in this treatment are advised to ask their treating clinicians whether it would be worth trying to access this drug by travelling to the USA.

There have been multiple promising immunotherapies for advanced prostate cancer that have been insufficiently effective to be approved for use in Australia. However, there are many clinical trials in progress testing new treatments, combining treatments and selecting the most appropriate patients for immunotherapies. With luck, investment of resources and talented researchers working in this field, we hope that a prostate cancer immunotherapy will one day become a reality.

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