Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading
Abstract Background Despite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. T...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04064-z |
| _version_ | 1797853580099584000 |
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| author | Meir Azulay Michal Shahar Eitan Shany Eti Elbaz Sveta Lifshits Marie Törngren Adam Friedmann Robert Kramer Gunnar Hedlund |
| author_facet | Meir Azulay Michal Shahar Eitan Shany Eti Elbaz Sveta Lifshits Marie Törngren Adam Friedmann Robert Kramer Gunnar Hedlund |
| author_sort | Meir Azulay |
| collection | DOAJ |
| description | Abstract Background Despite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. Tumor-targeted superantigen (TTS) therapy may overcome this barrier to enhance therapeutic efficacy. TTS proteins, such as the clinical-stage molecule naptumomab estafenatox (NAP), increase tumor recognition and killing by both coating tumor cells with bacterial-derived superantigens (SAgs) and selectively expanding T-cell lineages that can recognize them. The present study investigated the efficacy and mechanism of action of repeated TTS (C215Fab-SEA) treatments leading to a long-term antitumor immune response as monotherapy or in combination with PD-1/PD-L1 inhibitors in murine tumor models. Methods We used syngeneic murine tumor models expressing the human EpCAM target (C215 antigen) to assess the efficacy and mechanism of action of repeated treatment with TTS C215Fab-SEA alone or with anti-PD-1/PD-L1 monoclonal antibodies. Tumor draining lymph nodes (TDLNs) and tumor tissues were processed and analyzed by immunophenotyping and immunohistochemistry. Isolated RNA from tumors was used to analyze gene expression and the TCR repertoire. Tumor rechallenge and T-cell transfer studies were conducted to test the long-term antitumor memory response. Results TTS therapy inhibited tumor growth and achieved complete tumor rejection, leading to a T-cell-dependent long-term memory response against the tumor. The antitumor effect was derived from inflammatory responses converting the immunosuppressive TME into a proinflammatory state with an increase in T-cell infiltration, activation and high T-cell diversity. The combination of TTS with ICB therapy was significantly more effective than the monotherapies and resulted in higher tumor-free rates. Conclusions These new results indicate that TTSs not only can turn a “cold” tumor into a “hot” tumor but also can enable epitope spreading and memory response, which makes TTSs ideal candidates for combination with ICB agents and other anticancer agents. |
| first_indexed | 2024-04-09T19:52:57Z |
| format | Article |
| id | doaj.art-54bd572181154e1994748f438bb9e68f |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T19:52:57Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-54bd572181154e1994748f438bb9e68f2023-04-03T05:38:54ZengBMCJournal of Translational Medicine1479-58762023-03-0121112210.1186/s12967-023-04064-zTumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreadingMeir Azulay0Michal Shahar1Eitan Shany2Eti Elbaz3Sveta Lifshits4Marie Törngren5Adam Friedmann6Robert Kramer7Gunnar Hedlund8NeoTX Therapeutics LTDNeoTX Therapeutics LTDNeoTX Therapeutics LTDNeoTX Therapeutics LTDNeoTX Therapeutics LTDActive Biotech ABNeoTX Therapeutics LTDNeoTX Therapeutics LTDNeoTX Therapeutics LTDAbstract Background Despite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. Tumor-targeted superantigen (TTS) therapy may overcome this barrier to enhance therapeutic efficacy. TTS proteins, such as the clinical-stage molecule naptumomab estafenatox (NAP), increase tumor recognition and killing by both coating tumor cells with bacterial-derived superantigens (SAgs) and selectively expanding T-cell lineages that can recognize them. The present study investigated the efficacy and mechanism of action of repeated TTS (C215Fab-SEA) treatments leading to a long-term antitumor immune response as monotherapy or in combination with PD-1/PD-L1 inhibitors in murine tumor models. Methods We used syngeneic murine tumor models expressing the human EpCAM target (C215 antigen) to assess the efficacy and mechanism of action of repeated treatment with TTS C215Fab-SEA alone or with anti-PD-1/PD-L1 monoclonal antibodies. Tumor draining lymph nodes (TDLNs) and tumor tissues were processed and analyzed by immunophenotyping and immunohistochemistry. Isolated RNA from tumors was used to analyze gene expression and the TCR repertoire. Tumor rechallenge and T-cell transfer studies were conducted to test the long-term antitumor memory response. Results TTS therapy inhibited tumor growth and achieved complete tumor rejection, leading to a T-cell-dependent long-term memory response against the tumor. The antitumor effect was derived from inflammatory responses converting the immunosuppressive TME into a proinflammatory state with an increase in T-cell infiltration, activation and high T-cell diversity. The combination of TTS with ICB therapy was significantly more effective than the monotherapies and resulted in higher tumor-free rates. Conclusions These new results indicate that TTSs not only can turn a “cold” tumor into a “hot” tumor but also can enable epitope spreading and memory response, which makes TTSs ideal candidates for combination with ICB agents and other anticancer agents.https://doi.org/10.1186/s12967-023-04064-zNaptumomab estafenatoxImmune checkpoint inhibitorsProgrammed cell death 1 receptorT-cell receptorsMemory T lymphocytesImmunotherapy |
| spellingShingle | Meir Azulay Michal Shahar Eitan Shany Eti Elbaz Sveta Lifshits Marie Törngren Adam Friedmann Robert Kramer Gunnar Hedlund Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading Journal of Translational Medicine Naptumomab estafenatox Immune checkpoint inhibitors Programmed cell death 1 receptor T-cell receptors Memory T lymphocytes Immunotherapy |
| title | Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading |
| title_full | Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading |
| title_fullStr | Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading |
| title_full_unstemmed | Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading |
| title_short | Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading |
| title_sort | tumor targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading |
| topic | Naptumomab estafenatox Immune checkpoint inhibitors Programmed cell death 1 receptor T-cell receptors Memory T lymphocytes Immunotherapy |
| url | https://doi.org/10.1186/s12967-023-04064-z |
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