Novel Therapies for Cervical Cancer

Cervical cancer is the fourth most common female cancer worldwide and one of the top three cancers to affect women younger than 45. Currently, the standard treatment options for cervical cancer are surgery, radiotherapy, chemotherapy and targeted therapy, but the results are not satisfactory for patients with advanced cervical cancer. In particular, the options after initial treatment failure are very limited and the response rate is very low, between 4% and 14%. More effective treatment options are urgently needed.

FDA-Approved Drugs for Cervical Cancer

1. Avastin - Monoclonal Antibody

On August 14, 2014, The U.S. Food and Drug Administration approved Avastin (bevacizumab), a humanized anti-VEGF monoclonal antibody, in combination with chemotherapy drugs paclitaxel and cisplatin or in combination with paclitaxel and topotecan to treat patients with persistent, recurrent or late-stage (metastatic) cervical cancer.

avastin-global-MOA

Figure 1. Avastin Mechanism of Action, source: reference [1]

2. TIVDAK - Antibody-Drug Conjugates (ADCs)

Tisotumab vedotin is a novel ADC drug containing a monoclonal antibody targeting tissue factor (TF) and a microtubule disruptor, monomethyl auristatin E (MMAE). TF is aberrantly expressed in a variety of solid tumors, promoting tumor growth, angiogenesis and accelerating tumor metastasis. Tisotumab vedotin targets TF-expressing cells to deliver MMAE to induce direct cytotoxicity and bystander killing of neighboring cells.

Tisotumab-Vedotin-MOA

Figure 2. Mechanism of action of tisotumab vedotin

On September 20, 2021, the U.S. FDA granted accelerated approval for TIVDAK™ (tisotumab vedotin-tftv) for the treatment of adult patients with recurrent or metastatic cervical cancer whose disease has progressed during or after chemotherapy. Based on the results of the innovaTV 204 trial, the ORR was 24% (25/101), with a broader population independent of PD-L1 expression levels. Notably, TIVDAK™ is the first and currently the only approved antibody-drug conjugate (ADC) for cervical cancer.

3. Keytruda - PD-1 Inhibitor

On October 13, 2021, the FDA approved a new indication for Pembrolizumab (Keytruda) in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). To date, pembrolizumab remains the only FDA-approved PD-1 drug for treating cervical cancer, covering both second-line and first-line use.

Novel Immunotherapies in Development for Cervical Cancer

Tumor-infiltrating lymphocyte (TIL) therapy

TIL cell therapy is a type of adoptive cellular therapy leveraging the patient’s own immune system to treat tumors. The TILs are isolated from tumor tissue by biopsy or surgery, reprogrammed in the lab to recognize and attack cancer cells and expanded to a large number in vitro with interleukin-2 (IL-2), and then infused back into the patient so they can start attacking cancer cells.

TIL

Figure 3. Schematic representation of the production process for TIL therapy. Source: https://doi.org/10.1186/s12916-021-02006-4

In May 2019, the FDA granted breakthrough therapy designation to LN-145, TIL therapy for treating recurrent, metastatic, or persistent cervical cancer with disease progression on or after chemotherapy.

The designation is based on data from the ongoing phase II innovaTIL-04 (NCT03108495) trial, the latest results of which was presented at the 2019 ASCO Annual Meeting. Data showed that the TIL therapy had an overall response rate (ORR) of 44% in patients with advanced cervical cancer, which consisted of 1 complete response, 9 partial responses, and 2 unconfirmed partial responses. The disease control rate was 89% at a median follow-up of 3.5 months.

T cell receptor-engineered T cell (TCR-T) therapy

TCR-T is a novel cellular immunotherapy technology that uses bioengineering techniques to make its own immune killer T cells more recognizable and achieve precise tumor killing. This novel therapy allows physicians to engineer the most appropriate target for each patient's tumor and different types of T cells, individualizing treatment and offering patients greater hope for remission.

TCR-T

Figure 4. Adoptive T cell therapy. Source: https://doi.org/10.3389/fimmu.2021.658753

Recently, a specific targeted MAGE A3/A6TCR-T therapy named KITE-718 showed excellent efficacy in 17 cases of metastatic solid tumors. Among them, 4 patients with cervical cancer showed varying degrees of remission. One patient with metastatic cervical cancer who received radiation therapy and 6 cycles of cisplatin for primary cervical cancer and lymph node metastasis achieved complete remission with complete tumor disappearance, and the efficacy lasted for more than 29 months.

Conclusion

With the development of novel therapeutic modalities such as immunotherapy and targeted therapies in recent years, new advances have been made in the treatment of cervical cancer, significantly improving the prognosis of patients with cervical cancer, especially in cases where conventional chemoradiotherapy has failed. Despite the great promise shown by these therapies, they are not free of limitations and potential side effects, and further investigations are still needed to optimize the regimens used with these therapies and to determine which patients are most likely to benefit from them.

References:
[1] Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593-4599.
[2] Oncology Overview: Investigational Autologous TIL Immunotherapy LN-145 for Cervical Cancer, https://www.pharmacytimes.com/view/oncology-overview-investigational-autologous-til-immunotherapy-ln-145-for-cervical-cancer