B7-H3: A new target for prostate cancer immunotherapy

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B7-H3: A new target for prostate cancer immunotherapy

B7-H3: A new target for prostate cancer immunotherapy.

Although we have made great strides in the treatment of prostate cancer (PC) over the decades , prostate cancer (PC) is the second most commonly diagnosed cancer worldwide and the fifth leading cause of cancer death in men , prostate cancer There is still huge room for improvement in diagnosis and treatment.

In 2020 alone, there will be an estimated 1,414,000 new cases of prostate cancer and 375,304 associated deaths worldwide.

Prostate cancer is the most frequently diagnosed cancer in 112 countries and the leading cause of cancer death in 48 countries. Notably, the burden of prostate cancer should increase as the population ages and the economy grows.

Currently available therapies for the cure of PC remain localized: surgery or radiation therapy . Unfortunately, metastatic progression of PC ultimately leads to cancer-related death in most patients.

Therefore, a better understanding of PC treatment for relapse and the development of new approaches to advanced PC remain research frontiers that require significant investment.

In the treatment history of PC, from androgen deprivation therapy to targeted therapy for prostate cancer, some remarkable successes have been achieved to some extent.

The first FDA-approved tumor therapeutic vaccine is the antigen-presenting cell immunotherapy sipuleucel-T targeting prostatic acid phosphatase, which was approved in 2010 for asymptomatic or minimally symptomatic metastatic castration resistance PC (mCRPC) patients.

Since then, scientists have demonstrated the ability to induce potent antitumor immune responses against a variety of malignancies, including colorectal, melanoma, and lung cancer, by inhibiting immune checkpoints targeting the CTLA-4 and PD-1 pathways.

As the respective pioneers of CTLA-4 and PD-1 immunotherapy, James Allison and Tasuku Honjo jointly won the 2018 Nobel Prize in Physiology or Medicine.

Unfortunately, after some early clinical treatments (monotherapy or combination therapy), targeting CTLA-4 or PD-1/PD- L1 checkpoint blockade does not produce meaningful clinical responses in most patients with advanced PC.

Interestingly, there is increasing evidence that another member of the B7 family of immunomodulatory type 1 transmembrane glycoproteins ( including PD -L1 [B7-H1] and PD-L2 [B7-DC] ) known as B7 Members of -H3 may be suitable immune-blocking targets for PC therapy.

Studies have found that B7-H3 is more highly expressed than PD-L1 in PC , but relatively lower in normal tissues, so B7-H3 may be an attractive therapeutic target.

Furthermore, B7-H3 is the only immune checkpoint known to be directly regulated by the androgen receptor (AR).

AR occupancy was higher in PC and CRPC compared with normal prostate tissue, but not IFN-induced regulation, suggesting that PD-L1 and B7-H3 checkpoints may have distinct immune niches.

In this issue of European Urology ( “European Urology”), Guo Christina et al published a research paper entitled “”. The authors report the expression signature of B7-H3 protein during the progression of hormone-sensitive PC (HSPC) to CRPC, the association of B7-H3 expression with PC genomics, and the anti-B7-H3 antibody-drug conjugate (ADC) DS – Preclinical activity of 7300a.

B7-H3: A new target for prostate cancer immunotherapy

The present study provides evidence that corroborates previous findings that B7-H3 is highly expressed in both HSPC and CRPC states. Using matched HSPC and CRPC biopsies from the same patients, the researchers demonstrated that membrane-localized B7-H3 (mB7-H3) was expressed in biopsies from most HSPC (97%) and CRPC (93%) patients.

However, B7-H3 expression was not associated with patient survival outcomes, nor were the median expression of mB7-H3 and the proportion of B7-H3-positive tumors significantly different between matched HSPC and CRPC biopsies.

These findings suggest that if B7-H3 testing is accompanied by a diagnostic, similar to PD-L1 testing, new metastatic biopsies may not be required because B7-H3 levels may remain relatively constant.

Instead, we can rely on archival biopsies to measure baseline B7-H3 expression levels, which has been an important issue in PC research since patients may have only difficult-to-biopsy bone disease.

Interestingly, despite the high overall expression level of B7-H3 in PC tissues, the authors found some tumor cells that did not express B7-H3 in most of the biopsies examined, and found that B 7 – H3 Positive and negative tumor cells are mostly distributed in the range of one to two cell diameters.

The close spatial correlation between B7 -H3-positive and negative tumor cells suggests that consideration of B7-H3-targeting PC therapies may have important potential.

Because this spatially tight distribution allows for a bystander-killing effect, as is the case with the B7-H3-ADC (DS-7300a) under investigation and similar B7 – H3- targeted duocycin-based ADCs in clinical development phenomena observed in .

In addition, this work independently validated that the D9M2L monoclonal antibody targeting the conserved extracellular IgV1 -like domain of human B7- H3 can be used for tissue expression analysis of B7-H3, as recently reported by Mendes et al.

Furthermore, the low expression of B7-H3 in CRPC with neuroendocrine features is also consistent with the positive correlation between B7-H3 and AR expression, as similar findings were reported recently.

There is already evidence that B7-H3 may have immunosuppressive effects, although the data are somewhat uncertain. In this study, the authors observed a lower density of infiltrating CD3+ lymphocytes in tumors with high expression of mB7-H3 in PC cells, supporting this notion.

Furthermore, the finding that B7-H3 is highly expressed in tumors with deleterious DNA damage response gene alterations is intriguing, but the reliability of the conclusions is limited by the small sample size and lack of causal information.

Of course, this study has some additional limitations. For example, the sample size of the entire study was small, and readers should keep this in mind when accepting all of the research conclusions in this paper.

The negative association analysis between B7-H3 and neuroendocrine PC was based on only 4 of 98 samples from the original cohort, and the selection criteria for the other 18 evaluated patients were unclear.

Similar concerns were raised regarding the negative correlation analysis between B7-H3 and SPOP mutations. As the authors acknowledge, the use of immunodeficient CRPC patient-derived xenograft mouse models limited their ability to understand on-target/non-tumor toxicity, as B7-H3 is assumed to have an immunomodulatory role and each model represents a different The uniqueness of the patients by disease state may limit the generalizability of the results.

Nonetheless, Guo Christina et al. reported interesting findings regarding B7-H3 in PC. The development of precisely targeted drugs has always been very complex, requiring scientists to expend a lot of effort to identify suitable targets for specific disease processes.

However, this study and some previous studies suggest that B7-H3 may be a promising therapeutic target. Moreover, before the drug targeting B7-H3 is finally pronounced by the FDA, researchers still have a lot of work to do.

In fact, there are several ongoing trials of B7-H3-targeted ADCs and B7-H3 immunomodulatory approaches in PC that will hopefully help us gain more definitive insights in the near future (NCT04145622, NCT05280460, NCT03729596, NCT02923180, NCT05293496 and NCT05551117).

Reference:

Christina Guo. et al. B7-H3 as a Therapeutic Target in Advanced Prostate Cancer.

https://doi.org/10.1016/j.eururo.2022.09.004

B7-H3: A new target for prostate cancer immunotherapy

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