Cervical cancer is the fourth most common female cancer worldwide. This article focuses on FDA-approved therapies and novel immunotherapies in development for cervical cancer.

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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.
Figure 1. Avastin Mechanism of Action, source: reference [1]
2. TIVDAK - Antibody-Drug Conjugates (ADCs)

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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.
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

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

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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.
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.

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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-l
n-145-for-cervical-cancer
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Antibody–Drug Conjugate Payloads: MMAE & MMAF
The Bystander Effect of ADCs
FDA Approves Tivdak - First Tissue Factor (TF)-Targeted Antibody Conjugate Drug
(ADC)