Precision Immunotherapy For Prostate Cancer Therapy
Further discovery of new genes to target heterogeneous TME through genomics/deep sequencing will play a significant role in the successful personalized treatment. Furthermore, a combination therapy of Kristen rat sarcoma viral oncogene inhibitor and existing immunotherapies to target KRAS mutation-induced neoantigens in mutant KRAS tumors will be another multimodal therapeutic regimen. Hence, combination of multimodal immunotherapy that is personalized based on cancer genomics would lead to more effective interventions.
Immunotherapy And Local Treatments
Radiation treatment may have a systemic role by activating the immune system, stimulating immune priming , and improving response to immunotherapy.
A phase 12 study assessing ipilimumab±radiotherapy in mCRPC disease showed a 29% rate of non-progressive disease with the treatment combination after a median follow-up of 15.7 months . In this trial, metastasis-directed radiotherapy was given at a single dose of 8 Gy per target bone lesion at 2448 h before the first ipilimumab dose.
A phase 3 study included patients with post-docetaxel mCRPC and bone metastasis and randomized patients to receive bone-directed radiotherapy with ipilimumab or placebo . All patients received a single dose of radiotherapy of 8 Gy for at least one, and up to five, bone lesions. Radiotherapy was done within the 2 days before initiation of the study drug regimen, and palliative radiotherapy was allowed for any bone lesion while on study. The median follow-up was 9.9 months in ipilimumab group and 9.3 months in placebo group. Median overall survival was 11.2 and 10.0 months , respectively, without significant difference . Median PFS was 4.0 months for ipilimumab group vs. 3.1 for placebo group . Post hoc analysis suggested that ipilimumab might provide the most benefit in patients with favorable prognostic features, specifically in patients without visceral metastasis. The rates of grade 34 AEs were 59% for ipilimumab group vs 41% for placebo group.
Neuroendocrine Prostate Cancer: A Growing Threat
Neuroendocrine prostate cancer, or NEPC, makes up about 20% of advanced, treatment-resistant prostate cancer cases, and its incidence is on the rise. Many cases of prostate cancer are treatable with surgery and radiotherapy. In its initial stages, the cancerâs growth and survival requires signaling through the tumor cellsâ androgen receptor, which responds to hormones like testosterone. This makes androgen-deprivation therapies, which block testosterone and related hormones, a potent weapon against disease that isnât cured by surgery or chemotherapy.
In the last few decades, such therapies have dramatically extended lifespan for men whose cancer recurs or resists initial forms of treatment. But theyâre not a cure. Eventually, prostate tumors develop resistance to anti-androgen therapies and evolve ways to continue growing and spreading without the androgen receptor. Some tumors do this by taking on molecular characteristics common to neuroendocrine cells, which are cells that interact with nerve cells to release hormones.
This presents patients, oncologists and prostate cancer researchers with a new problem.
âNeuroendocrine prostate cancer is a growing problem because there really aren’t many effective therapies,â Dr. Diana DeLucia, the postdoctoral fellow in Leeâs lab who spearheaded the work. âSo we need to develop novel ways to target tumors of patients that have neuroendocrine prostate cancer.â
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Remission And The Chance Of Recurrence
A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having no evidence of disease or NED.
A remission can be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. Although there are treatments to help prevent a recurrence, such as hormonal therapy and radiation therapy, it is important to talk with your doctor about the possibility of the cancer returning. There are tools your doctor can use, called nomograms, to estimate someone’s risk of recurrence. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence.
In general, following surgery or radiation therapy, the PSA level in the blood usually drops. If the PSA level starts to rise again, it may be a sign that the cancer has come back. If the cancer returns after the original treatment, it is called recurrent cancer.
When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence, including where the recurrence is located. The cancer may come back in the prostate , in the tissues or lymph nodes near the prostate , or in another part of the body, such as the bones, lungs, or liver . Sometimes the doctor cannot find a tumor even though the PSA level has increased. This is known as a PSA recurrence or biochemical recurrence.
Power Analysis And Statistical Methods
Patients with PSA progression on enzalutamide are unlikely to have a spontaneous PSA response without a change in therapy. We deemed that a 25% response rate to pembrolizumab observed here would be worthy of further study. Using a null hypothesis of 5% and alternate hypothesis of 25%, 25 evaluable patients were needed with 90% power and a one-sided alpha of 0.05. To account for potential drop-out, we enrolled 28 subjects. Descriptive statistical analyses were conducted for all variables of interest. Kaplan-Meier method was used to estimate the distribution of overall survival and PFS. Exact binomial test was used to determine whether the response rate was significantly > 5%. Statistical analysis for clinical endpoints were conducted in R V.3.4.3.
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Immunoconjugate Therapy Using Mabs
Immunoconjugate therapy utilizes an immune substance, such as a mAb that is chemically linked to a cytotoxic substance such as a toxin, radioisotope, or drug.
Radioimmunotherapy
A combination of radiation and immunotherapy , RIT involves using a small amount of radionuclide combined with a mAb, resulting in the formation of a radiopharmaceutical. mAbs recognize and bind to specific cell surface antigens, thus enabling the delivery of high amounts of radiation specifically into the tumor and minimizing off-target effects. Though a promising idea, RIT has shown consistent results only in hematological and lymphoid malignancies. However, PCa is unique among solid tumors as it is radiosensitive, expresses highly specific antigens that are easily targetable, and even a small volume of metastatic disease in bone marrow and lymph nodes can be picked up easily on imaging and accessed by circulating antibodies.99 These properties can help PCa surpass the usual hindrances to application of radioimmunotherapy in solid malignancies.
In a similar study, Yttrium-90-labeled J591 was used in men with CRPC. Only 2 of the 29 patients in this study experienced objective measurable disease response, which was reflected by a > 50% fall in PSA levels, which lasted for about 8months, whereas 6 patients were reported to have stable PSA levels.103 Both the previously mentioned trials showed successful targeting of skeletal and soft tissue metastatic disease in most patients.102,103
Tumor Mutational Burden And Pd1/pd
PCa is characterized by a low tumor mutational burden , thus revealing a poor collection of neoepitopes crucial for immune cell attraction to the tumor sites, epitopeMHC interactions and activation of TILs by antigen-presenting cells . PCa has distinctly fewer mutations than breast , bladder and colorectal cancer , or melanoma . Even in castration-sensitive or -resistant disease, TMB is only as high as 2.08 and 4.02 per Mb, respectively . Due to a low TMB and T-cell-mediated inflammation, the probability that PCa responses to anti-PD1/PD-L1 treatment is weak .
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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.
Immunotherapy And Parp Inhibitor
Durvalumab is a human IgG1-K monoclonal antibody that targets PD-L1. Olaparib is a PARP inhibitor approved for patients with mCRPC carrying homologous recombination repair gene alteration. Preclinical data have suggested a synergistic effect between PARP and checkpoint inhibitors. A phase II, open-label trial has assessed this combination in multiple cohorts of heavily pretreated mCRPC patients . Seventeen patients were enrolled and received durvalumab plus olaparib. Median rPFS was 16.1 months. The 1-year PFS rate was 83.3% for patients with alteration in DNA damage response gene vs. 36.4% for those without mutations . Most common treatment-related grade 3 or 4 AEs were anemia, lymphopenia, infection, and nausea.
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Chimeric Antigen Receptor T
Another emerging field that has shown promise is chimeric antigen receptor T-cell therapy. CAR-T therapy involves taking a patients T cells, engineering them to express a T cell receptor directed against a certain antigen, expanding the cells, and reinfusing them back into the patient. CAR-Ts directed against CD19 have been approved for the treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. CAR-Ts are also designed to express costimulatory domains, which may interact with ligands or receptors on antigen-presenting cells, tumor cells, or on the T cell itself .
Complex Tumor Microenvironment Of Pca
Given the dynamic nature of immune cell types, the impact of the immune system on PCa is remarkably complex. Because high-grade PCa is characterized by low-level tumor infiltration of lymphocytes,12,116 the interactions between innate and adaptive immunity are not well understood.117 Macrophages and Treg cells have been associated with aggressive pathology, high rates of recurrence after prostatectomy, and worse distant metastatic-free survival.77,118,119 On the other hand, mast cells, NK cells, and DCs are negatively associated with tumor progression,120,121 and have been shown to confer improved distant metastatic-free survival.77 TILs in PCa may be dysfunctional and not capable of producing an immune response as suggested by examination of over 1500 resected PCa specimens wherein a greater TIL population was associated with a lower metastasis-free survival.77 Low tumor-associated antigen expression, DNA mismatch repair gene defects, subdued expression of MHC classI, lack of phosphatase and tensin homolog protein, and poor IFN1 signaling are some key processes that play a role in this complex tumor environment.122 One study revealed that the average mutation frequency in PCa is almost 10 times lower than melanoma, which may explain the significant difference in response to immunotherapy between the two malignancies.
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Targeted Immunotherapy For Deadly Prostate Cancer Shows Promise In Preclinical Test
Using a targeting molecule to concentrate toxic chemotherapy in tumors could hold potential as a treatment for an aggressive subtype of advanced prostate cancer, according to work published November 16 in the journal Clinical Cancer Research. Scientists at Fred Hutchinson Cancer Research Center show that some neuroendocrine prostate cancer cells have high levels of a specific protein marker, and that using this marker to guide chemotherapy to these cancer cells eradicates human tumors growing in mice.
âWeâre developing a targeted treatment for a disease that otherwise didnât have any targeted treatments. Thatâs huge,â said Hutch prostate cancer researcher Dr. John Lee, the paperâs senior author. âIt takes into account that not all cancers of a specific tissue are the same. You really have to delve deeper to understand how one personâs disease may be different from anotherâs.â
He is working with Immunomedics, Inc., the manufacturer of the experimental therapy and now a subsidiary of Gilead Sciences, Inc., to initiate an early stage clinical trial in patients with neuroendocrine prostate cancer. Lee and his team have no financial stake in the potential treatment.
The experimental drug is an antibody-drug conjugate, in which a drug is attached to an antibody, a specialized immune protein that can bind to other proteins. Scientists have modified them to carry cancer-killing drugs to specific cellular targets.
A New Treatment For Advanced Prostate Cancer Improves Survival In Phase 3 Clinical Trial
- By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases
Radiation therapy is getting more precise, enabled by technologies that make it easier to kill tumors while sparing their surrounding tissues. Some newer therapies are even given intravenously instead of by machines, and they deliver radiation particles directly to the cancer cell itself. One of these new therapies a sort of smart bomb targeted at malignant cells is now generating promising data for men with the most aggressive prostate cancer.
In early June, investigators reported results from a phase 3 clinical trial showing that among men who received the experimental treatment, there was nearly a 40% reduction in deaths over the course of the study, compared to men who did not.
The treatment is called lutetium-177-PSMA-617, or LuPSMA, and it has two components: a compound that targets a cancer cell protein called prostate-specific membrane antigen, or PSMA, and a radioactive particle that destroys the cells. Healthy prostate cells don’t contain PSMA, or do at very low levels. And some men with prostate cancer have more of the protein than others. Doctors can detect the protein using a specialized imaging scan.
Results after 21 months showed that cancer progression was delayed for longer among the LuPSMA-treated men: 8.7 months on average versus 3.4 months among the controls. The treatment was also associated with better overall survival: 15.3 months versus 11.3 months.
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Search Strategy And Selection Criteria
This study comprehensively analyzed all the active or completed clinical trials of drug therapeutics for PC from January, 2010, to January 1, 2020, worldwide and in China. The details of the trials were obtained from Pharmaprojects, a drug development database developed by INFORMA . Pharmaprojects harbors more than 40,000 public sources, including Clinicaltrials.gov and Gene Therapy Clinical Trials Worldwide, as well as many other sources. The following search keywords were used: .
Why Are Scientific Publications Important
Scientific publications, commonly referred to as papers, are how scientists share their own work or review the work done by others. In order to be accepted for publication in a journal, they must first be approved by experts in the field . As such, they are a testament to a scientific teams credibility and the quality and reliability of their work. Both the stamp of approval given by a publication and the ability for other scientists to learn about and build upon a teams research are important steps to take lab science closer to real-life benefits for humans.
This publication is an original research article, in which a team of scientists share their own work and discoveries.
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Ctla4 As A Potential Immune Checkpoint Inhibitor
Ipilimumab is an immune checkpoint inhibitor that blocks CTLA4, expressed on the surface of cytotoxic T cells, preventing T-cellmediated antitumor immune responses . Administration of this monoclonal antibody has already been approved by the FDA as cancer immunotherapy agents . Initial clinical trial with ipilimumab monotherapy was discontinued at phase III due to only a marginal improvement of patient OS when compared with the placebo arm . As an alternative strategy, ongoing clinical trials for mCRPC adopt combinations of immune checkpoint inhibitors. For instance, a phase II clinical trial, CheckMate 650, was initiated to study a combination of ipilimumab and nivolumab in patients with mCRPC who developed resistance to androgen receptor targeted therapies . However, recently Cancer Discovery 2019 reported that the combination of the two drugs resulted in only 25% of objective response rate . In addition, discontinuation of the therapy in the study population was reported due to the disease progression and increased side effects . Another phase III trial, in which patients with mCRPC that had progressed after Taxol chemotherapy received radiotherapy targeting bone metastasis followed by ipilimumab treatment, resulted in prolonged median OS . Furthermore, the result showed that OS rate at 1 year in patients who received ipilimumab therapy was 46.5%, compared with 40.8% in the placebo group.
Finding Small Amounts Of Prostate Cancer Using Imaging And Psma
NCI-supported researchers are developing new imaging techniques to improve the diagnosis of recurrent prostate cancer. A protein called prostate-specific membrane antigen is found in large amountsand almost exclusivelyon prostate cells. By fusing a molecule that binds to PSMA to a compound used in PET scan imaging, scientists have been able to see tiny deposits of prostate cancer that are too small to be detected by regular imaging. The Food and Drug Administration has approved two such compounds for use in PET imaging of men with prostate cancer.
This type of test is still experimental. But the ability to detect very small amounts of metastatic prostate cancer could help doctors and patients make better-informed treatment decisions. For example, if metastatic cancer is found when a man is first diagnosed, he may choose an alternative to surgery because the cancer has already spread. Or doctors may be able to treat cancer recurrenceeither in the prostate or metastatic diseaseearlier, which may lead to better survival.
As part of the Cancer Moonshot, NCI researchers are testing whether PSMA-PET imaging can also identify men who are at high risk of their cancer recurring. Such imaging may eventually be able to help predict who needs more aggressive treatmentsuch as radiation therapy in addition to surgeryafter diagnosis.
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