Immunotherapy in Advanced Prostate Cancer—Light at the End of the Tunnel?

Amsberg, Gunhild von; Alsdorf, Winfried; Karagiannis, Panagiotis; Coym, Anja; Kaune, Moritz; Werner, Stefan; Graefen, Markus; Bokemeyer, Carsten; Merkens, Lina; Dyshlovoy, Sergey A.

doi:10.3390/ijms23052569

Cited by 15 publications

(7 citation statements)

References 192 publications

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“…A variety of immunotherapies are under development, including peptide-based cancer vaccines (for example, [ 47 ]). Although useful in cancers such as melanoma, bladder cancer, and non-small cell lung cancer, clinical studies of immunotherapy in prostate cancer have been largely disappointing [ 48 ], perhaps because of the “cold” tumor microenvironment [ 49 ]. A recent systematic review explains some of the many obstacles to be overcome [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Analysis of Clinical Trials and Review of Recent Advances in Therapy Decisions for Locally Advanced Prostate Cancer

Williams¹

2023

JPM

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Despite the implementation of screening and early detection in many countries, the prostate cancer mortality rate remains high, particularly when the cancer is locally advanced. Targeted therapies with high efficacy and minimal harms should be particularly beneficial in this group, and several new approaches show promise. This article briefly analyses relevant clinical studies listed on ClinicalTrials.gov, combined with a short literature review that considers new therapeutic approaches that can be investigated in future clinical trials. Therapies using gold nanoparticles are of special interest in low-resource settings as they can localize and enhance the cancer-cell killing potential of X-rays using equipment that is already widely available.

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Section: Resultsmentioning

confidence: 99%

Analysis of Clinical Trials and Review of Recent Advances in Therapy Decisions for Locally Advanced Prostate Cancer

Williams¹

2023

JPM

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“…In addition, patients with aggressive or neuroendocrine transdifferentiation often have lower PSMA expression and thus have limited access to this treatment. Immunotherapeutic treatment approaches have so far fallen short of the high expectations placed in them [ 32 ]. The first promising data for patients with visceral metastasis were now demonstrated for a combination with cabozantinib and atezolizumab.…”

Section: Discussionmentioning

confidence: 99%

Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer

Amsberg

Zilles

Mansour

et al. 2022

IJMS

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Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.

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“…Prostate cancer is the most common lethal male malignancy, with high morbidity associated with metastatic disease. Unlike other tumor histologies where immunotherapy has been transformative for patient outcomes, results in prostate cancer have been disappointing ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors

Archer,

Brailey,

Song

et al. 2024

Clinical Cancer Research

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Purpose: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. Experimental Design: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. Results: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. Conclusions: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.

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Immunotherapy in Advanced Prostate Cancer—Light at the End of the Tunnel?

Cited by 15 publications

References 192 publications

Analysis of Clinical Trials and Review of Recent Advances in Therapy Decisions for Locally Advanced Prostate Cancer

Analysis of Clinical Trials and Review of Recent Advances in Therapy Decisions for Locally Advanced Prostate Cancer

Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors

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