Novel stimulation strategy with autologous tumor cells to generate T cell receptor‐engineered T cells in esophageal squamous cell carcinoma

Esophageal cancer is one of the most common cancers worldwide, associated with more than 400 000 cancer‐related deaths each year.1 It is a global concern, especially in China. Around 200 000 new cases of esophageal cancer are diagnosed annually in China which account for 50% of all esophageal cancer diagnosed worldwide.2, 3 The most prevalent type of esophageal cancer is esophageal squamous cell carcinoma (ESCC).4 The prognosis of ESCC is poor due to its late diagnosis and lack of effective systemic therapeutic strategy. Recently, advancements in immunotherapy have led to encouraging results for ESCC.5 On 30 July 2019, the U.S. Food and Drug Administration approved pembrolizumab, an immunotherapy drug, to treat advanced ESCC patients with programmed cell‐death protein 1 (PD‐L1) expression.

Adoptive cellular therapy (ACT, also known as cellular immunotherapy) is a form of immunotherapy that uses the autologous tumor‐cognate lymphocytes to eliminate the tumor. Since genetically‐modified T cells have been shown to have significant antitumor effects in certain hematological malignancies,6 this has led to an upsurge in research on ACT for solid tumors.7, 8, 9 T cell receptor‐engineered T cell (TCR‐T) therapy is one of the most important ACTs, which has been proven to be an effective type of immunotherapy in a variety of tumors.10 Tumor‐specific T cell receptors (TCRs) determine the antitumor efficacy of TCR‐Ts. They are usually isolated from the T cells which are activated by tumor‐specific antigens. Theoretically, tumor‐specific antigens generated by somatic mutations can activate tumor‐reactive T cells and induce antitumor immune response.11 In fact, few tumor‐specific antigens per patient can induce antitumor immune response12 as most tumor‐specific antigens come from non‐coding regions.13 Therefore, there is an urgent need to find more tumor‐reactive antigens, especially for cancer species with low tumor mutation burden.

Autologous tumor cells (ATCs), which express various tumor antigens, may be the current best stimulants for activating tumor‐reactive T cells.14 Moreover, previous studies have found that CD137, a specific biomarker of activated T cells, could be used to isolate and enrich tumor‐reactive T cells.15 Based on these findings and considerations, Tan et al.16 attempted to isolate tumor‐reactive TCRs by stimulation of ESCC ATCs, CD137‐sorted tumor infiltrating lymphocytes (TILs) and subsequently introduced the TCRs into peripheral blood lymphocytes to generate tumor‐reactive TCR‐Ts. Their findings have recently been published in the Journal for Immunotherapy of Cancer, entitled “Isolation of T cell receptor specifically reactive with autologous tumour cells from tumour‐infiltrating lymphocytes and construction of T cell receptor engineered T cells for esophageal squamous cell carcinoma”.16

In that study, the authors obtained one tumor specimen from a 63‐year‐old ESCC patient and isolated several TIL subgroups from different anatomical sites of the specimen. In order to screen TILs with potential antitumor activities, they cocultured the isolated cells with ATCs separately. The TILs were found to be able to produce a significantly higher level of interferon gamma (IFNγ) after 48 hours of coculture compared to their control counterparts without coculture that were stimulated with ATCs, and CD8⁺CD137⁺ TILs were further isolated by cell sorting after stimulation. Their TCRs were obtained via single‐cell PCR amplification and identified by single‐cell TCR sequencing. The expression plasmids of the first ranked TCR were transfected into peripheral blood lymphocytes to generate TCR‐Ts. The ability to accurately identify ESCC cells and the potential cytotoxicity that mediate tumor regression were further evaluated. As the authors expected, TCR1‐expressing TCR‐Ts could specifically identify and kill ESCC cells both in vitro and in vivo.

TIL‐adoptive transfer has been demonstrated to be one of the most effective treatments for cancer; however, most cancer patients do not respond to this treatment. The most likely reason for this might be that the TILs used for ACT are exhausted because they are highly differentiated and usually undergo large‐scale in vitro expansion before being used for treatment. Tan and colleagues successfully isolated tumor‐specific TCRs from the exhausted TILs and introduced them into peripheral blood lymphocytes with normal immune function to produce tumor‐reactive TCR‐Ts with stronger antitumor response. This new treatment strategy is similar to the analogy of taking sophisticated weapons from tired soldiers, handing them to motivated ones so that they can better fight the tenacious enemy. In addition to ESCC, this treatment strategy may be applicable to other cancers, especially to cancer patients without prior knowledge of specific epitopes. Since the present study only enrolled one ESCC patient, it is difficult to fully evaluate the efficacy and success rate of obtaining tumor‐reactive TCR‐Ts. Therefore, more ESCC patients must be recruited to validate the effectiveness and safety of this treatment strategy in future studies. Additionally, in the study by Tan et al. the authors only used a low‐throughput PCR‐based sequencing method to identify tumor‐reactive TCRs, which is inadequate for clinical applications. Therefore, high‐throughput sequencing should be used to screen tumor‐reactive TCRs in the future.

Disclosure

The author declares no competing interests.