Immunotherapy May Be Effective For Some Prostate Cancers
by Beth Israel Deaconess Medical Center
In recent years, cancer immunotherapy has been effective in treating patients with immunogenic, or so-called “hot” tumors with increased levels of inflammation and the presence of immune cells in and around the tumors. Prostate cancer, however, is considered a “cold” tumor, with few immune cells recognizing and infiltrating prostate malignancies. Accordingly, prostate cancer has been found to respond poorly to the class of immunotherapies known as immune checkpoint inhibitors.
In previous work, a team led by medical oncologists at Beth Israel Deaconess Medical Center identified a subset of prostate cancers that exhibited characteristics more typical of hot cancers. Now, in a paper appearing in the journal Clinical Cancer Research, researchers report that about a quarter of localized prostate cancers may demonstrate these immunologic traits, suggesting that a substantial number of patients with prostate cancer may, in fact, benefit from immunotherapies.
Einstein and colleagues, including co-corresponding author Steven Balk, MD, Ph.D., a physician at BIDMC, focused on two characteristics that make traditionally immunogenic cancers susceptible to immunotherapy: PD-L1 expression and T cell infiltration. PD-L1 is a protein involved in tumor evasion of the immune system. T cells are the sentinels of the immune system, patrolling the body for potential pathogens or disease.
More information:Clinical Cancer Research
Extended Data Figure 3 Significant Combination Efficacy By Cabozantinib And Icb Observed In Chimaeras Generated From Jh58
a, Experimental design for JH58 chimaeras, similar to the JH61 chimaera experiments. b, Longitudinal MRI images from representative chimaeras in control or combination cohorts. Red contour denotes area of prostate tumour. c, Strong anti-tumour effect by combination therapy in JH58 chimaeras shown by prostate tumour mass, lymph node metastasis scores and lung micrometastasis number . **P< 0.01, Students t-test. d, e, Quantification of tumour cell proliferation by Ki67 immunohistochemistry with representative images. Anterior prostate and dorsolateral prostate were quantified separately. f, g, Quantification of tumour cell apoptosis by cleaved caspase 3 immunohistochemistry with representative images. Scale bar, 100m. In c, d, and f, data represent mean±s.d. *P< 0.05, **P< 0.01, ***P< 0.001, compared with control using Students t-test.
Extended Data Figure 7 Cabozantinib Or Bez235 Suppress Secretion By Pca Cells Of Several Cytokines That Promote Mdsc Activity
a, Quantification of intratumoural cytokine levels in CRPC chimaera tumours with indicated treatment using cytokine array . Numerals 19 represent CCL5, CCL12, CCL21, CD40, CD142, HGF, IGFBP-6, IL-1ra, and VEGF, respectively. b, Quantification of intratumoural cytokine levels in Dasa+ICB combination-treated CPPSML chimaera CRPC with mouse cytokine assay, with image and relative intensity of the numbered cytokines shown . c, Experimental design for MDSC culture in the presence of PCa conditioned medium. d, Cytokine array results for conditioned medium from CPPSML PCa cell lines treated with vehicle, Cabo , or BEZ for 12h . Boxed cytokine is CCL5. e, Effect of supplementation of individual cytokines to the conditioned medium from PCa cell lines treated with Cabo or BEZ on Arg1, Cybb, Ncf1, and Ncf4 from cultured MDSCs . f, g, Chemical structure and synthesis of allosteric CXCR1/2 antagonist SX-682 . For details, please refer to the corresponding section in Methods. In b, e, and f, data represent mean±s.d.
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Chemotherapy And Immunotherapy Combination In Advanced Prostate Cancer
Susan Slovin, MD, PhD
Susan Slovin, MD, PhD
Dr. Slovin is a medical oncologist at the Sidney Kimmel Center for Prostate and Urologic Cancers of Memorial Sloan-Kettering Cancer Center in New York, New York.
Address correspondence to: Susan Slovin, MD, PhD, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 Phone: 646-422-4470 Fax: 212-988-0701 E-mail: [email protected]
Introduction
Castrate-resistant prostate cancer represents a spectrum of diseases on which prostate cancer progresses despite low levels of testosterone induced by chemical or surgical castration.1 Such patients are sometimes referred to as hormone refractory, although secondary and tertiary antiandrogen therapy may still have a beneficial effect.
Although docetaxel remains the first-line standard of care for metastatic CRPC due to its demonstrated survival benefit when compared with mitoxantrone,2 both cabazitaxel and abiraterone recently received approval from the US Food and Drug Administration as second-line CRPC therapies in patients who have already received docetaxel. These agents each offer about a 4-month survival benefit. Another new entry in the CRPC therapy arena is the active immunotherapy sipuleucel-T .
Rationale for Combining Chemo- and Immunotherapies
Premise: Metastatic Tumors Escape Cell-Mediated Immune Response
Combining Chemotherapy and Immunotherapy: the Reality
Could Immunotherapy Finally Break Through In Prostate Cancer
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 persons 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 to approve this vaccine called sipuleucel-T raised hopes for a surge of cancer treatments that use the bodys 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 symptoms.
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Can We Train The Immune System To Attack Prostate Cancer We’re Funding These Researchers To Find Out
Weve invested £1.7 million into five exceptional immunotherapy projects led by top prostate cancer research teams across the UK. Meet the team below.
Immunotherapy is an ingenious, effective treatment for many cancers. But it’s had limited success in men with prostate cancer. Are we about to change that?
What is immunotherapy?
Immunotherapy treatments work by harnessing the power of your own immune system to treat cancer. With the help of these treatments, the immune cells can be trained to recognise intruding cancer cells and attack them.
Your immune system constantly patrols your body to detect and destroy any cells that are abnormal. This includes many early pre-cancerous cells. However, cancer cells will try to outwit the immune system by disguising themselves in a series of ways with genetic changes or surface proteins.
Simon Grieveson, our Head of Research, says: Immunotherapy has revolutionised the treatment of many types of cancer, but so far this approach has only been successful in small numbers of men with prostate cancer. Thats why were investing in research to accelerate progress in this field and help develop more effective treatments for men diagnosed with prostate cancer. Funding innovative studies that tackle prostate cancer from new angles is vital to stop so many men dying from the disease.
We caught up with researchers from three of these new projects to find out how their work could benefit men.
Professor Katherine Vallis, University of Oxford
Current Mechanisms Underly Icis Responses In Prostate Cancer
A small subset of mCRPC patients with a microsatellite instability and dMMR phenotype exhibit high-tumoral mutation burden and higher levels of tumor infiltrating lymphocytes . It has been reported that some cancer patients with dMMR, including mCRPC, colorectal, and endometrial cancers display exceptional responses to the anti-PD-1 pembrolizumab . These results led to the approval of pembrolizumab by FDA for the treatment of all MMR-deficient metastatic tumors, which was based on a predictive biomarker alone, but not on tumor histology.
Other molecular alterations in prostate cancer may also affect the immune responses, which are clinically relevant. Calagua reported that prostate tumors in a subset of aggressive localized prostate cancer cases express PD-L1 along with a high density of tumor infiltrating lymphocytes but without high microsatellite instability or CDK12 alterations. Exhausted progenitor CD8+ T cells and differentiated effector T cells as indicated by positive PD-1 and transcription factor TCF1 staining were founded in the tumor infiltrating lymphocytes, which are expandable by ICIs . Areas within tumor tissue with MHC-II+ cells and CD8+TCF1+ T cells were also identified to be comparable with prostate cancer cases with dMMR, suggesting the existence of sufficient antigen-presenting cells niches. In addition, genomic losses of RB1, BRCA2, and CHD1 are common features of this subset of prostate cancer cases with potential immunogenicity.
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Past Current And Future Of Immunotherapies For Prostate Cancer
- 1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- 2Department of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- 3Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
If Treatment Does Not Work
Recovery from cancer is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or terminal.
This diagnosis is stressful, and for some people, advanced cancer may be difficult to discuss. However, it is important to have open and honest conversations with your health care team to express your feelings, preferences, and concerns. The health care team has special skills, experience, and knowledge to support patients and their families and is there to help. Making sure a person is physically comfortable, free from pain, and emotionally supported is extremely important.
People who have advanced cancer and who are expected to live less than 6 months may want to consider hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment, including a hospital bed, can make staying at home a workable option for many families. Learn more about advanced cancer care planning.
After the death of a loved one, many people need support to help them cope with the loss. Learn more about grief and loss.
Read Also: Nccn Guidelines Prostate Cancer 2022
Combination Of Immune Checkpoint Inhibitors
Anti CTLA-4 and anti PD-1 both are immune checkpoint inhibitors, but act on different receptors and affect the immune response in different ways, therefore, they may have synergistic effect when combined together. Ipilimumab and nivolumab combination therapy have been tested in Melanoma, which showed improved outcomes as compared to independent therapies of both. But there were grade 3 to 4, adverse reaction in 55% of population . Currently phase 1 and phase 2 studies are going on regarding combination therapy in CRPC, which have been described in Tables 3 and 4. But increased efficacy of the combination has to weighed against increased side effect profile.
What Are The Benefits
There are many reasons your doctor might think immunotherapy is a good choice for you:
Immunotherapy may work when other treatments donât. Some cancers donât respond well to radiation or chemotherapy but start to go away after immunotherapy.
It can help other cancer treatments work better. Other therapies you have, like chemotherapy, may work better if you also have immunotherapy.
It causes fewer side effects than other treatments. This is because it targets just your immune system and not all the cells in your body.
Your cancer may be less likely to return. When you have immunotherapy, your immune system learns to go after cancer cells if they ever come back. This is called immunomemory, and it could help you stay cancer-free for a longer time.
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Parp Inhibition In Prostate Cancer
PARP is an enzyme which initiate single stranded DNA repair. In patient with underlying DNA repair problem, if we inhibit PARP there will be no DNA repair and cell will die. This is the basic principle of action of PARP inhibitors. One study showed that genomic testing from bone and soft tissue metastasis of CRPC has DNA repair alterations. There are aberrations in androgen receptor , TP53, PTEN, BRCA1/2 and ATM genes. It also showed that 89% of these are clinically actionable DNA mutation and frequency of these aberrations increase with progression of disease . Olaparib is an oral PARP inhibition, which is approved for BRCA1/2 mutant ovarian cancer . As prostate cancer patients also have this mutation, active PARP inhibition can be a promising treatment. In a phase 2 study where mCRPC patients not responding to standard therapy are treated with Olaparib and mutational status was assessed by genomic sequencing. It showed that 33% patients have high response to Olaparib therapy and it was associated with defect in DNA repair gene. BRCA and ATM mutations were found in 10% and 12% of patients respectively, out of 49 patients. All patients with BRCA mutations and 80% of ATM mutations had clinical response to Olaparib. It was a small study but it prompted a new therapy for CRPC .
Table 5
Vaccine Immunotherapy In Early Stages Of Cancer
Vaccine immunotherapy is not a direct cancer cell lytic therapy, basically it enhances the immune system to fight against cancer cells and which is a slow process and has to go through multiple steps. And as cancer progresses it has suppressive effect on immune system, and with advanced stages of cancer reactivation of immune system will not be an easy task. Clinical data involving several tumor types have shown that vaccine immunotherapy works best in early stages of disease with limited tumor burden . It has been shown that there is threefold increase in inflammatory cells in tumor microenvironment when they are treated with Sipuleucel-T prior to radical prostatectomy .
Biomarkers
Failure of individual immune check point inhibitors raised the question whether expression of PD-1/PD-L1/CTLA-4 is biomarker for efficacy of immune checkpoint inhibitors. Immune biomarkers are required to increase the efficacy and to reduce the side effect profile. Further studies need to be conducted to look for more specific biomarkers.
Prostate cancer antigens
Immunotherapy vaccines target the antigens which are present normally on prostate like PAP, PSA, prostate specific cell antigen. Prostate cancer undergoes significant somatic mutations and several mutated proteins can serve as a neoantigens . If we can find and target these new mutated proteins, efficacy and specificity of vaccine will significantly improve.
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What Are The Risks
Immunotherapy holds a lot of promise as a cancer treatment. Still, it can cause some problems.
You might have a bad reaction. The area where the medication goes into your body could hurt, itch, swell, turn red, or get sore.
There are side effects. Some types of immunotherapy rev up your immune system and make you feel like you have the flu, complete with fever, chills, and fatigue. Others could cause problems like swelling, weight gain from extra fluids, heart palpitations, a stuffy head, and diarrhea. Most of the time, these ease up after your first treatment.
It can harm organs and systems. Some of these drugs can cause your immune system to attack organs like your heart, liver, lungs, kidneys, or intestines.
It isnât a quick fix. In some cases, immunotherapy takes longer to work than other treatments. Your cancer may not go away quickly.
It doesnât work for everyone. Right now, immunotherapy works for less than half the people who try it. Many people only have a partial response. This means your tumor could stop growing or get smaller, but it doesnât go away. Doctors arenât sure yet why immunotherapy helps only some people.
Your body could get used to it. Over time, immunotherapy may stop having an effect on your cancer cells. This means that even if it works at first, your tumor could start to grow again.
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New Approach To Fighting Prostate Cancer
SIR-T therapy uses different receptors that more closely resemble the bodys natural T-cells.
Dr. Chaudhary and his team tested thousands of prototypes over an eight-year period to develop receptors that can safely attack solid tumors, including prostate cancer.
Initial tests in mice yielded promising results. In May, the California Institute for Regenerative Medicine a publicly funded state initiative for stem cell research awarded Dr. Chaudhary $5.8 million to conduct preclinical studies.
This could lead to applying for Food and Drug Administration approval to begin clinical trials of SIR-T therapy in humans.
Dr. Chaudharys lab has also received grants from the U.S. Department of Defense to study SIR-T therapys effectiveness against melanoma, kidney cancer, lymphoma and a different molecule involved in prostate cancer.
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Potential Mechanisms Of Resistance Of Prostate Cancer To Immunotherapy
To date, clinical trials of immune therapy for PCa patients have focused on metastatic prostate cancer, with specific efforts being made for progressing therapies for patients with castration resistant disease. A dysfunctional immune system in men with mPC may account for unresponsiveness to current immunotherapy. Patients with metastatic prostate cancer have dysfunctional cellular immunity and an increased immune suppressive tumor microenvironment. These compromised immune functions include, but are not limited to, impaired function and renewal of natural killer cells , and impaired expression of CD3 in NK and T cells , a key signaling molecule for T-cell receptor and NK cell activating receptors. Metastatic CRPC patients also have reduced T cell frequency in the circulation , although it is not clear whether it is the outcome of AST or tumor-mediated modulation of T cell homeostasis. Men with mPC also have increased suppressive phenotypes of myeloid suppressor cells and regulatory T cells in the circulation, as well as in the tumor microenvironment . The compromised cellular immunity and highly immune suppressive tumor microenvironment likely explain the reported low infiltration of effective immune cell types in the primary tumor in men with PCa. Whether lack of immune infiltration is due to inability of effector NK and T cells homing to the tumor, or survival in the local tumor microenvironment, is an open question.