Immune Checkpoint Blockade With Chemotherapy
Chemotherapy by killing tumor cells increases tumor neoantigens, disrupts immune-suppressive pathways, and enhances effector T cell responses . This suggests possible improved responses with a combination of chemotherapy and ICI therapy. In 41 chemotherapy-naive mCRPC patients treated with nivolumab plus docetaxel combination, the ORR was 36.8% with one CR and six PRs and the confirmed PSA response rate was 46.5% . Similarly, in the KEYNOTE-365 trial chemotherapy plus ICI blockade , ORR based on RECIST 1.1 was 18% with 7 PRs, 5/7 of responses lasted 6 months with median DOR of 6.7 months range and the PSA response rate was 28% Also, radiological PFS was 8.3 months and OS was 20.4 months .
Study Design And Treatment
The present trial is a multicenter, single-arm, proof-of-concept , phase II study. aimed to evaluate the efficacy and safety of combination therapy of niraparib plus nivolumab or pembrolizumab in patients with solid cancer involving HRR gene mutations. This study is conducted as a tumor-agnostic trial for patients with metastatic urothelial carcinoma , metastatic renal cell carcinoma , metastatic gastric cancer , metastatic esophageal cancer , metastatic head and neck cancer , and metastatic melanoma . HRR gene mutations were determined by tumor tissue analysis including FoundationOne CDx, OncoGuide NCC oncopanel, and Caris Molecular Profiling . In this study, FoundationOne liquid CDx, Guardant 360, and Caris Assure are also used to screen patients harboring HRR gene mutations using ctDNA tests in blood samples . The HRR genes are defined as BRCA1, BRCA2, ATM, CDK12, CHEK2, PALB2, BARD1, BRIP1, CHEK1, FANCL, RAD51B, RAD51C, RAD51D, and RAD54L. This trial has been registered in the Japan Registry of Clinical Trials .
Fig. 1
Patient Characteristics And Clinicopathological Data
Ninety-six prostate cancer tissue specimens were obtained retrospectively from patients performed with RP or transrectal ultrasound-guided prostatic biopsy in the Urology Department of The Fourth Affiliated Hospital of Guangxi Medical University between 2012 and 2015. These patients were diagnosed by two senior pathologists. The mean age of prostate cancer patients was 70âyears . None of them received surgical castration, drug castration, radiotherapy or chemotherapy before the operation. According to the EAU urological disease diagnosis guidelines, patients were divided into the following groups: age < â60, 60â69, 70â79 and > â80 the serum TPSA value: < â4, 4â10, 10â20 and > â20 Gleason score < â7, 7 and > â7 clinical stage T1 + T2 and T3 + T4 groups and grade of risk factors: low-risk group , medium risk group and high-risk group . In the control group, 44 BPH patients were collected from the same period. The mean age was 70.6 ± 6.9 years. There was no significant difference in age between the two groups. Our study was approved by the Institutional Ethics Review Board of The Fourth Affiliated Hospital of Guangxi Medical University. All participants signed an informed consent for the use of the samples during hospitalisation. The clinical data of all these participants were retrospectively obtained from the hospital electronic patient record system.
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Immune Checkpoint Blockade With Parp Inhibitors
Poly ADP-ribose polymerase inhibition can potentiate responses to PD-1/PD-L1 inhibition via a number of mechanisms including increased TMB secondary to unrepaired DNA damage , enhanced PD-L1 expression, and immune cell infiltration into the tumor microenvironment. . In the durvalumab plus olaparib trial involving 17 mCRPC patients after progression on androgen receptor blockade therapy, median rPFS for all patients was 16.1 months , 53% patients had a PSA decline of 50% and 4/9 patients had radiographic response per RECIST v.1.1. Patients with mutations in DDR genes responded better with an 83.3% probability of 12-month progression-free survival compared to 36.4% in those without mutations . Similarly, olaparib with pembrolizumab in molecularly unselected mCRPC patients showed an OS of 14 months , PSA response rate of 9%, and ORR of 8% with 2 partial responses. Both responses lasted 12 months and the median response duration was not reached at the time of data reporting .
Intermittent But Not Daily Bay1082439 Treatment Turns Pten
The potent effect of BAY1082439 in inhibiting cancer cell-intrinsic immunosuppressive activity prompted us to test whether BAY1082439 treatment could turn Pten-null prostate cancer to T cell-inflamed and promote T cell-mediated anti-tumor immunity in vivo. Unfortunately, daily 75mg/kg BAY1082439 treatment led to significantly decreased tumor- and spleen-associated CD45+, CD8+ T and CD4+ T cell numbers , which could be detrimental for T cell-mediated anti-tumor immunity even if cancer cell-intrinsic immunosuppression could be alleviated.
Fig. 2: Intermittent but not daily BAY1082439 treatment turns Pten-null prostate tumors to T cell-inflamed.
We then tested the long-term effects of 75mg/Kg daily and 180mg/Kg intermittent dosing schedules on 10 week-old castrated Pten-null prostate cancer mice when prostate developed high grade PIN/adenocarcinoma phenotypes, . BAY-D or BAY-I treatment did not cause significant and persistent animal body weight reduction or reach humane endpoint .
Despite of a significant reduction in overall dosage in the BAY-I cohort , both BAY-D and BAY-I showed equal potency in decreasing cancer cell burden after 4 weeks of treatment without significant change the pathological features associated with Pten-null CRPC, including nuclear atypia, loss or partially loss of CK5 basal cells and SMA staining and immune cell infiltration .
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Adoptive T Cell Therapy And Immune Checkpoint Blockade
Adoptive T cells are tumor-specific T cells that are isolated from the patient, expanded ex vivo, and reinfused back into the patients . NeoTCR-P1 is a form of adoptive T cell therapy where apheresis-derived T cells are engineered to express an autologous T cell receptor of the native sequence. These T cells can then target a neoepitope that is unique to the patients tumor cells and presented in association with human leukocyte antigen receptors. NeoTCR-P1 has been studied in combination with nivolumab based on signals that this combination may have meaningful activity .
Tumor Antigen Not Equal To The Tme
Prostate cancer is often referred to as a bland or cold disease, Slovin explained however, a lack of expression on immune cells is only the tip of the iceberg from discovering and acting upon targets. Several immunosuppressive factors that within the tumor microenvironment prevent the transformation to a hot or inflamed environment, including cancer-associated fibroblasts, T regulatory cells, and inhibitory molecules such as adenosine.
The presence of CD8-positive T cells in the tumor microenvironment has been described in 3 scenarios: desert, in which T cells are absent from the tumor and its periphery excluded, in which the T cells have accumulated but do not efficiently infiltrate the tumor and inflamed, in which the T cells infiltrate but their effects are inhibited.3 Approaches to overcome resistance to facilitate immune infiltration including oncolytic viruses which promote T-cell priming, adoptive cellular therapies that promote T-cell expansion, and TFG inhibitors which promote T-cell trafficking and infiltration.1,3
interesting because despite the information presented , which indicated that these tumors were highly responsive to nivolumab or , investigators of the phase 2 trial didnt see any signal, Slovin said. very surprising.
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Other Promising Treatment Approaches
CAR-T cell therapy is a novel method of re-engineering native T cells, combining the extracellular antigen recognition domains of a monoclonal antibody and a T-cell receptor activating signaling domain: this technique enhances the antigen-antibody complex formation in response to cytotoxic tumor cell proliferation . So, antigen recognition is not MHC-restricted, like the T cell receptor-mediated antigen identification . Interesting results have been reported in B-cell malignancies , while solid tumors are trickier.
In castrate metastatic PC, early-phase trials found that CAR-T cell therapy may target the prostate-specific membrane antigen , a glycosylated type-II membrane protein that is upregulated in aggressive PCs . However, the substantial failure of CAR-T cell response may relate to CAR-T cell inactivation and/or possible exclusion from the tumor mass, tumor-stroma interactions, and PC propensity to metastasize preferentially to the bone. Moreover, CAR-T cells may produce proinflammatory cytokines, increasing PD-L1 expression on tumor cells, and impairing the recruitment/sustained activation of effector T cells: immunomodulation is likely required to increase CAR T-cell efficacy against solid tumors .
Studies Evaluating Single Agent Pd
KEYNOTE-028, a phase Ib study has reported an objective response rate of 17.4% with pembrolizumab in a cohort of 23 heavily pretreated mCRPC patients with measurable disease and 1% PD-L1 expression in tumor or stromal cells. The response was a partial response in 4 patients and 3/4 experienced parallel biochemical response . Following the favorable side effect profile in the KEYNOTE-28 trial, pembrolizumab has been subsequently studied as a monotherapy or in various combinations.
The KEYNOTE-199 trial evaluated the activity of pembrolizumab as monotherapy in three mCRPC cohorts. Cohort 1 enrolled patients with PD-L1 positive tumor and measurable disease, cohort 2 enrolled PD-L1 negative tumors and measurable disease, while cohort 3 enrolled non-measurable, bone metastatic disease regardless of the PD-L1 status. Median OS was 9.5 months , 7.9 months , 14.1 months and confirmed PSA response was 6% of 124 patients, 8% of 60 patients, and 2% of 59 patients in cohorts 1, 2, and 3, respectively. Observed ORR was modest , with a median duration of 16.8 months and 55% had ongoing responses at data cutoff. Other interesting observations in this trial were similarity of outcomes regardless of PD-L1 status and no clear relationship between responses to pembrolizumab and DNA damage repair gene mutation status as determined by whole-exome sequencing .
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Predictors Of Response To Immune Checkpoint Blockade
Though PD-L1 expression on tumor cells and stromal cells within the tumor may predict favorable responses to PD-1/PD-L1 blockade therapy, this is not always true. There exists considerable intratumoral heterogeneity with regards to PD-L1 expression along with inter-assay variability, limiting PD-L1 expression as the sole predictor of response to PD-1/PD-L1 blockade . PD-L1 expression in the tumor is not static as it may increase with tumor progression . Also, PD-L1 expression can be modulated by radiation and chemotherapy . Moreover, concomitant genomic alterations such as homologous recombination deficiency , microsatellite instability-high or mismatch repair-deficiency , and POLE/POLD1 mutations can increase the responsiveness to ICI by increasing the tumor mutation burden and expression of neoantigens .
PD-L1/PD-L2 positivity in dendritic cells of patients who had progressed on enzalutamide is increased compared to patients who were enzalutamide naive or who had responded to enzalutamide . Androgen ablation also upregulates adaptive immunity in prostate cancer by increasing naive T cell expansion . In a phase II trial of 28 men with mCRPC treated with pembrolizumab and enzalutamide after progressing on enzalutamide, a PSA response was obtained in about 18% of patients, and an objective response in 25% of patients who had measurable disease. None of the three responders had detectable PD-L1 expression .
Data Evaluation Of Pd
PD-L1-stained slides were scored for PD-L1 immune cell -positivity and PD-L1 tumour cell -positivity . The data was analysed by senior pathologists specialising in PD-L1 evaluation in various tumour entities. PD-L1 IC-positivity was defined as staining in granulocytes, lymphocytes, macrophages and dendritic cells of any intensity within the tumour area. PD-L1 TC-positivity was defined as membranous PD-L1 staining of any intensity in all detectable tumour cells on the slide. In addition, the combined positive score was determined, which is calculated as the total number of PD-L1 positive TC and IC in the tumour area divided by the total number of viable TC multiplied by 100% . PD-L1 expression values 1% and a CPS 1 were defined as positive. For the CD8 and granzyme B double staining, the primary CD8 antibody , Dako) and the primary granzyme B antibody , Dako) were blended, followed by counterstaining with hematoxylin, dehydration and mounting of the slides.
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Combination Strategies With Pd
The clinical data surrounding inhibition of PD-1/PD-L1 in prostate cancer is evolving. In the past, I have written a couple of articles about both single-agent and combination approaches for metastatic castration-resistant prostate cancer .1, 2 The field has evolved to the point where we recognize that single-agent PD-1/PD-L1 inhibition is unlikely to yield a major benefit for an unselected population. In the KEYNOTE-199 trial, pembrolizumab yielded 5% and 3% objective response rates in patients with PD-L1 positive and negative tumors, respectively.3
Similarly, in the IMbassador250 randomized phase 3 trial, atezolizumab did not offer an overall survival advantage when combined with enzalutamide over enzalutamide alone.4 With that said, there are still multiple randomized phase 3 trials for patients with mCRPC that have pending results. For example, KEYNOTE-641, KEYNOTE-921, and KEYLYNK-010 are testing whether pembrolizumab combined with enzalutamide, docetaxel, or olaparib, respectively, for unselected populations, will lead to patient benefit .
Highlighted Trials for patients with mCSPC
Written by: , Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, WashingtonReferences
Immunotherapy For Prostate Cancer Includes Two Fda
The prostate is a small, walnut-shaped gland that is part of the male reproductive system. The prostate is located just below the bladder, where it surrounds the top portion of the urethra . The main function of the prostate gland is to secrete fluid that nourishes and protects sperm.
As the second most common male cancer in the world, prostate cancer affects roughly 1.3 million people and kills more than 360,000 people each year, which represents about 4% of all cancer deaths worldwide. In the United States alone, there will be roughly 248,000 new cases and more than 34,000 deaths in 2021. Prostate cancer, the eighth leading cause of cancer-related deaths, will impact an estimated 1 in every 7 men in their lifetimes.
In its early stages, prostate cancer is highly treatable, with five-year survival rates close to 100%. Once prostate cancer has metastasized, however, the 5-year survival rate falls to less than 30%, highlighting a significant need for more effective treatment of advanced stage disease.
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Biomarker Analyses And Translational Research
ctDNA analysis using a targeted next-generation sequencing will be performed at baseline, Cycle 2, and after treatment discontinuation. We will also perform three types of analysis to investigate predictive biomarkers of response to this combination therapy. First, the expression level of PD-L1, a well-known biomarker of the clinical response to ICIs in cancer tissues, will be evaluated. Second, we will perform T cell repertoire analysis based on next-generation sequencing to determine whether T cell receptor diversity in the peripheral blood can serve as a useful indicator of response to combination therapy. Third, we will perform a mass spectrometry-based quantitative proteomic analysis using plasma to identify candidate proteins as potential predictive biomarkers.
Side Effects Of Checkpoint Inhibitors
Some of the more common side effects of checkpoint inhibitors include:
- Muscle and joint pain
Other, more serious side effects occur less often:
Infusion reactions: Some people might have an infusion reaction while getting these drugs. This is like an allergic reaction, and can include fever, chills, flushing of the face, rash, itchy skin, feeling dizzy, wheezing, and trouble breathing. Its important to tell your doctor or nurse right away if you have any of these symptoms while getting one of these drugs.
Autoimmune reactions: By targeting a checkpoint protein, these drugs remove one of the safeguards on the body’s immune system. Sometimes the immune system responds by attacking other parts of the body, which can cause serious or even life-threatening problems in the lungs, intestines, liver, hormone-making glands, kidneys, or other organs.
Its very important to report any new side effects to someone on your health care team as soon as possible. If serious side effects do occur, treatment may need to be stopped and you might be given high doses of corticosteroids to suppress your immune system.
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Influence Of Androgen Deprivation Therapy On The Pd
- 1Institute of Pathology, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
- 2National Center for Tumor Diseases Partner Site Dresden and German Cancer Center Heidelberg, Dresden, Germany
- 3Tumor and Normal Tissue Bank of the University Cancer Center , University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- 4Department of Urology, Technische Universität Dresden, Dresden, Germany
- 5Department of Urology, Mildred Scheel Early Career Center, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Studies Evaluating Single Agent Ctla
In phase III CA184-095 trial, high dose ipilimumab monotherapy did not show an improvement in median OS compared to the placebo in chemotherapy naïve minimally symptomatic mCRPC patients. But higher median progression-free survival , PSA response rates , and longer time to systemic nonhormonal cytotoxic therapy were observed compared to placebo, indicating antitumor activity. More treatment-related grade 3 to 4 adverse events were observed compared to the 3 mg/kg dose used in melanoma and there were 9 treatment-related deaths .
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Who Will Respond To Pd
Specific DNA changes in a tumor may help determine which patients are most likely to respond to treatment with PD-1 inhibitors, according to findings from a new study by researchers at Memorial Sloan Kettering Cancer Center.
The FDA has approved two PD-1 inhibitors: nivolumab and pembrolizumab . Both are part of a class of immunotherapy drugs known as checkpoint inhibitors.
Patient responses to checkpoint inhibitors have been highly variable, with some patients experiencing long-lasting tumor responses, but others having only short-lived tumor shrinkage or disease stabilization or no response at all.
The study, published March 12 in Science, showedthat patients with lung cancer whose tumor cells had high levels of DNA damageas measured by the number of genetic mutations that resulted in a changed proteinwere more likely to experience tumor shrinkage and had longer progression-free survival when treated with pembrolizumab than patients whose tumors had modest to little genetic damage.
The patients who had the strongest responses were those whose tumors had genetic mutations commonly associated with tobacco smoking, lead author Naiyer Rizvi, M.D., and his colleagues reported. Treatment efficacy also correlated with a high number of proteins expressed only on tumors, called neoantigens.