**6. Monoclonal antibodies and testicular cancer**

Testicular cancer is a disease of the male organ, testicles that produces the male hormones and sperms. Approximately 90% of testicular cancer start in the germ cells which make the sperm and are referred to as the Germ cell tumor (GCT). They are of two types: seminomas and non-seminomas. The testicular cancer are the solid tumors that can be treated by chemotherapy even in the metastatic condition. However, the role of immunotherapy is still under investigation. The incidence of Testicular cancer has observed an increasing trend in both America and Europe [25].

#### **6.1 Testicular cancer**

There are several trials that have been directed towards the Testicular cancer. Several of these trials are against the Immune check point inhibitors. Many case studies have reported immune checkpoint inhibition efficacy in refractory GCTs. However, the mechanism by which this occurs is not clear. Trials have been conducted with mAbs, nivolumab or pembrolizumab (both anti-PD-1 agents) on subjects with refractory GCT. The results are very inconvincing on a phase II trial of Adra et *al*. [26] who administered pembrolizumab to 10 refractory

**133**

gaining approvals and success.

treatment.

*Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management…*

GCT patients. Despite of the PD-L1 status there were no responses and hence this led to the termination of the trial. Although three of seven patients with refractory germ cell tumors treated with nivolumab or pembrolizumab did show response, there was partial remission. Some case reports did mention about the rapid progression of the disease with pembrolizumab on single dose and some 40% response with single dose of nivolumab. In a case study reported by Chi and Schweizer, treatment response to nivolumab was observed hence, use of single checkpoint inhibitors have been unstable in nature [27]. No responses were observed by nadal et al. for a case report on a study conducted using Nibolumabwith cabozantini and bipilimumab [28]. Due to inefficacy of single agent durvalumab, the monotherapy arm was closed for a study conducted by Raggi et al. [29] Hence the results of immune checkpoint inhibitor monotherapy studies are disappointing and hence need more evaluation in many more clinical

Penile Cancer is a disease in which a tumor growth occurs in the tissues of the Penis. Although the localized penile cancer can be treated by penectomy, the metastatic forms need better strategies to deal with such as the standard Chemotherapy or the novel Immunotherapy. About 95% of the penile cancers are squamous cell carcinomas and other forms include the sarcoma, melanomas and the basal cell carcinoma. Most of the penile cancer is caused by HPV (human papilloma virus) infection. Although the incidence of Penile cancer is only about 1 in every 1,00,000 individuals I America and Europe, several Immunotherapy drug trials are underway

Epidermal growth factor receptor is usually overly expressed in Penile squamous

cell carcinoma. EGFR amplification has been observed and thereby reported in a number of studies on primary penile squamous cell carcinoma. This amplification has been observed with poor prognosis in patients with penile squamous cell carcinoma and increased risk of recurrence. Considering this aspect, it has been chosen for treatment of systemic penile cancer. Immunotherapy towards EGFR target, includes monoclonal antibodies cetuximab and panitumumab [28]. In a study considering cetuximab either alone or with cisplatin, there was partial response. In another study considering cetuximab, panitumumab, and nimotuzumab about 50% of the patients showed response to treatment. However, this was a second line of

In addition to anti-EGFR therapy, immune checkpoint inhibitor drug trials of avelumab and pembrolizumab are under progress. These drugs are evaluating the role of PD- L1 and PD-1 inhibition with the above mentioned mAbs respectively, exclusively in penile carcinoma. The combination of PD-1 and cytotoxic T lymphocyte protein 4 (CTLA4) blockade might improve antitumour activity across multiple malignancies, including PSCC. However, the majority of the trials with patients suffering from penile carcinoma are basket trials that include because incidence of penile squamous cell carcinoma is very low [30]. In addition, Cetuximab, a chimeric monoclonal antibody is an epidermal growth factor receptor (EGFR) inhibitor and has still not received FDA approval for the treatment of penile cancer. Phase I trials of Nivolumab are also underway which is a conjunction of chemotherapy and lymphokine working against the HPV. As the frequency of this disease is very low, it has been difficult to conduct many trials. However, continual progress in the area of Immunotherapy with fewer trials has still been

*DOI: http://dx.doi.org/10.5772/intechopen.96911*

trials that shall be planned for future.

to strategize its importance.

**7. Monoclonal antibodies and penile cancer**

*Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management… DOI: http://dx.doi.org/10.5772/intechopen.96911*

GCT patients. Despite of the PD-L1 status there were no responses and hence this led to the termination of the trial. Although three of seven patients with refractory germ cell tumors treated with nivolumab or pembrolizumab did show response, there was partial remission. Some case reports did mention about the rapid progression of the disease with pembrolizumab on single dose and some 40% response with single dose of nivolumab. In a case study reported by Chi and Schweizer, treatment response to nivolumab was observed hence, use of single checkpoint inhibitors have been unstable in nature [27]. No responses were observed by nadal et al. for a case report on a study conducted using Nibolumabwith cabozantini and bipilimumab [28]. Due to inefficacy of single agent durvalumab, the monotherapy arm was closed for a study conducted by Raggi et al. [29] Hence the results of immune checkpoint inhibitor monotherapy studies are disappointing and hence need more evaluation in many more clinical trials that shall be planned for future.

## **7. Monoclonal antibodies and penile cancer**

Penile Cancer is a disease in which a tumor growth occurs in the tissues of the Penis. Although the localized penile cancer can be treated by penectomy, the metastatic forms need better strategies to deal with such as the standard Chemotherapy or the novel Immunotherapy. About 95% of the penile cancers are squamous cell carcinomas and other forms include the sarcoma, melanomas and the basal cell carcinoma. Most of the penile cancer is caused by HPV (human papilloma virus) infection. Although the incidence of Penile cancer is only about 1 in every 1,00,000 individuals I America and Europe, several Immunotherapy drug trials are underway to strategize its importance.

Epidermal growth factor receptor is usually overly expressed in Penile squamous cell carcinoma. EGFR amplification has been observed and thereby reported in a number of studies on primary penile squamous cell carcinoma. This amplification has been observed with poor prognosis in patients with penile squamous cell carcinoma and increased risk of recurrence. Considering this aspect, it has been chosen for treatment of systemic penile cancer. Immunotherapy towards EGFR target, includes monoclonal antibodies cetuximab and panitumumab [28]. In a study considering cetuximab either alone or with cisplatin, there was partial response. In another study considering cetuximab, panitumumab, and nimotuzumab about 50% of the patients showed response to treatment. However, this was a second line of treatment.

In addition to anti-EGFR therapy, immune checkpoint inhibitor drug trials of avelumab and pembrolizumab are under progress. These drugs are evaluating the role of PD- L1 and PD-1 inhibition with the above mentioned mAbs respectively, exclusively in penile carcinoma. The combination of PD-1 and cytotoxic T lymphocyte protein 4 (CTLA4) blockade might improve antitumour activity across multiple malignancies, including PSCC. However, the majority of the trials with patients suffering from penile carcinoma are basket trials that include because incidence of penile squamous cell carcinoma is very low [30]. In addition, Cetuximab, a chimeric monoclonal antibody is an epidermal growth factor receptor (EGFR) inhibitor and has still not received FDA approval for the treatment of penile cancer. Phase I trials of Nivolumab are also underway which is a conjunction of chemotherapy and lymphokine working against the HPV. As the frequency of this disease is very low, it has been difficult to conduct many trials. However, continual progress in the area of Immunotherapy with fewer trials has still been gaining approvals and success.

*Monoclonal Antibodies*

farina and his colleagues.

Many subjects did show adverse events [21].

mAbs,PD-L1 overexpression among patients was not significant. In another phase II clinical trial with subjects also receiving platinum-based chemotherapy showed a two-month progression-free period. In patients with PD-L1 overexpression compared to patients with low-expression, a difference in drug effects was observed.

Pembrolizumab has been showing positive responses in cases of advanced bladder cancer. It is a humanized monoclonal antibody used in the treatment of bladder cancer and is approved by the FDA and EAU. In a study conducted by on pembrolizumab by Bellmunt et al., it was observed that this mAb showed lower adverse events and longer survival by about 3 months which was significant when compared

to chemotherapy drugs such as docetaxel and paclitaxel [22]. In a case report mentioning the treatment with pembrolizumab as reported by McDermott et al., it was observed that adverse events were not observed after 8 months and hence suggested that pembrolizumab can be considered as a PD –I inhibitor [23]. In patients with DNA repair defects, pembrolizumab can also be considered for treatment. This drug not only reduced the risk of developing newer cancers but also prevented premalignant hyperplastic lesion. This shall be a rational therapy. Pembrolizumab is also shown better survival rates when compared to chemotherapy as mentioned

A novel murine monoclonal antibody KMP1 has been studied by cheng and his colleagues [24]. The study was conducted both in vitro and in vivo settings It identified the CD44 epitope on bladder cancer cells and bound to it due to O-linked glycosylation and thereby exhibit antitumor potential in both settings. Future studies may be recommended to understand the exact glycolsylation mechanism also produce humanized forms and also conjugate types for better therapeutics. Enfortumab vedotin delivers toxic drugs to tumors. It is an antibody-drug conjugate that targets the Nectin-4 pathway, it has been approved for further study in case of bladder cancer. Immunotherapy has significantly reduced the risk of recurrence for bladder cancer while also increasing the percentage of patients who see a complete response post-surgery. Investigational bladder cancer immunotherapies also have

the capacity change the outcomes positively for patients with this disease.

Testicular cancer is a disease of the male organ, testicles that produces the male hormones and sperms. Approximately 90% of testicular cancer start in the germ cells which make the sperm and are referred to as the Germ cell tumor (GCT). They are of two types: seminomas and non-seminomas. The testicular cancer are the solid tumors that can be treated by chemotherapy even in the metastatic condition. However, the role of immunotherapy is still under investigation. The incidence of Testicular cancer has observed an increasing trend in both America

There are several trials that have been directed towards the Testicular cancer.

Several of these trials are against the Immune check point inhibitors. Many case studies have reported immune checkpoint inhibition efficacy in refractory GCTs. However, the mechanism by which this occurs is not clear. Trials have been conducted with mAbs, nivolumab or pembrolizumab (both anti-PD-1 agents) on subjects with refractory GCT. The results are very inconvincing on a phase II trial of Adra et *al*. [26] who administered pembrolizumab to 10 refractory

**6. Monoclonal antibodies and testicular cancer**

**132**

and Europe [25].

**6.1 Testicular cancer**

## **8. Conclusion**

Immune status modification as strategy of cancer therapy does hold a significant place. Although, the conventional cancer treatments such as surgery, chemotherapy, and radiotherapy are still being referred to as the prominent ones, for some cancer types, immunotherapies are considered as first-line of treatment. One of the most important discoveries in the last several years in immunotherapy has been the development of immune checkpoint inhibitor, monoclonal antibodies that promote antitumor activity. T cells are a form of lymphocyte which are produced within the thymus and performs a crucial function in stimulating body's immune reaction to combat most cancers. They apprehend the overseas particles (antigens) with the aid of using particularly variable T cell receptor. Unlike antibody, the TCR cannot bind antigen and as a substitute it wishes to have peptides of the antigen proven to it with the aid of using an antigen presenting cell (APC). The molecules at the APC that gift the antigen are called as major histocompatibility complexes (MHC). Many stimulatory alerts also are wanted at this time. B7 is a form of peripheral membrane protein observed on activated antigen-providing cells (APC). This B7 on an APC can bind to cytotoxic T-lymphocyte-related antigen 4 (CTLA-4) developing an inhibitory sign and TCR activation. Once the activated T-cell receptor is within the tumor surroundings it is able to apprehend the antigen supplied with the aid of APC within the tumor. At this time, the programmed cell death protein 1 (PD-1) receptor also sends an inhibitory signal to the T-cell when the receptor binds to programmed cell death 1 ligand 1 (PD-L1), that's regularly expressed on tumor cells. Monoclonal antibodies act by inhibiting the binding PD-1 to PD-L1 and thereby boost body's immune response against the tumor cells.

Checkpoint inhibitors specifically goal PD-1/PD-L1) and CTLA4 Immune checkpoint efficacy is stricken by diverse factors, among which are tumor genomics, host germline genetics, PD-L1 levels, and intestine microbiome. Generally, in tumors, mutated or incorrectly expressed proteins are processed through the immunoproteasome into peptides which can be commonly loaded onto MHC molecules, which similarly now no longer usually are capable of eliciting CD8+ T cell reaction. This may also cause producing MHC-supplied immunogenic neoepitopes. It turned into proven, that after the intratumor heterogeneity rises, neoantigen-expressing clones emerge as greater homogenous with the differential expression of PD-L1.

There are number of FDA approved monoclonal antibodies, that are considered for the treatment of Urology oncology. These have been detailed in the **Table 1** and include FDA-approved PD-1 inhibitors such as nivolumab, pembrolizumab, cemiplimab, and FDA-approved PD-L1 such as atezolizumab, avelumab, and durvalumab. But all the open literatures do believe that combinatorial strategies with immune checkpoint therapies may provide a better survival benefit which have been demonstrated in various clinical trials. These can be in combination with radiation therapy, tyrosine kinase inhibitors and also many chemotherapeutic drugs. However, the response to immunotherapy with monoclonal antibodies varies subjectively and hence research into PD-L1 expression, gene signature expression, messenger RNA subtype, mutational and neoantigen load is essential to determine the varying response to monoclonal antibody immunotherapy. Although older modalities of treatment for cancer, has been extensively exploited, array of new drugs that offer hope of not only prolonging life but also curing significantly more patients in the future bring a ray of hope to the scientific world.

**135**

India

**Author details**

Maya Kulshekar1

and Murigendra B. Hiremath<sup>5</sup>

Belagavi, Karnataka, India

Chikodi, Karnataka, India

Dharwad, Karnataka, India

provided the original work is properly cited.

, Shridhar C. Ghagane2

1 Department of Biochemistry, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University), JNMC Campus,

3 Department of Zoology, KLES B.K. Arts, Science and Commerce College,

5 Department of Biotechnology and Microbiology, Karnatak University,

\*Address all correspondence to: shridhar.kleskf@gmail.com

Hospital and Medical Research Centre, Belagavi, Karnataka, India

2 Division of Urologic-Oncology, Department of Urology, KLES Dr. Prabhakar Kore

4 Department of Urology, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University), JNMC Campus, Belagavi, Karnataka,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*, Sridevi I. Puranik3

, Rajendra B. Nerli4

*Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management…*

*DOI: http://dx.doi.org/10.5772/intechopen.96911*

### **Conflict of interest**

The authors declare conflict of interest as None.

*Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management… DOI: http://dx.doi.org/10.5772/intechopen.96911*
