Author: Ferrer, Irene ; Jiménez-Reinoso, Anaïs ; Molero-Abraham, Magdalena ; Zugazagoitia, Jon ; Nuñez-Buiza, Ángel ; Blanco, Belén ; Garrido-Martin, Eva M. ; Pareja, Eduardo ; Díez-Alonso, Laura ; Ramírez-Orellana, Manuel ; Rodriguez-Peralto, José Luis ; Nehme-Álvarez, Daniel ; Domínguez-Alonso, Carmen ; Álvarez-Vallina, Luis ; Cirauqui, Cristina ; Ramírez-Fernández, Ángel ; Paz-Ares, Luis ; Tobes, Raquel ; González-Murillo, África

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TIL^STAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TIL^STAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR⁺ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4⁺ TIL bearing non-tumor dominant clonotypes.

14 Feb 2024·Science Translational MedicineQ1 · MEDICINE

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo

Q1 · MEDICINE

Article

Author: Gómez-Rosel, Marina ; Penela, Petronila ; Romencín, Paola A ; Bueno, Clara ; Pérez-Pons, Alba ; Río, Paula ; Mayado, Andrea ; Albitre, Ángela ; Jara, Maria ; Sanz, Laura ; Martín-Antonio, Beatriz ; Aguilar-Sopeña, Óscar ; Segura-Tudela, Alejandro ; Roda-Navarro, Pedro ; Blanco, Belén ; Jiménez-Reinoso, Anaïs ; Ramírez-Fernández, Ángel ; Orfao, Alberto ; Tapia-Galisteo, Antonio ; Martínez-López, Joaquín ; Perez-Amill, Lorena ; Díez-Alonso, Laura ; Anguita, Eduardo ; Martínez, Alba ; Hangiu, Oana ; Juan, Manel ; Menéndez, Pablo ; Valeri, Antonio ; Álvarez-Vallina, Luis ; Falgas, Aïda ; Solé, Francesc ; Rubio-Pérez, Laura ; Arroyo-Ródenas, Javier ; Almagro, Laura ; Domínguez-Alonso, Carmen ; García-Ortiz, Almudena

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

31 Dec 2022·OncoImmunologyQ2 · MEDICINE

Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies

Q2 · MEDICINE

ArticleOA

Author: Roda-Navarro, Pedro ; Aguilar-Sopeña, Óscar ; Segura-Tudela, Alejandro ; Blanco, Belén ; Ramírez-Fernández, Ángel ; Domínguez-Alonso, Carmen ; Díez-Alonso, Laura ; Álvarez-Vallina, Luis

Cancer immunotherapy strategies based on the endogenous secretion of T cell-redirecting bispecific antibodies by engineered T lymphocytes (STAb-T) are emerging as alternative or complementary approaches to those based on chimeric antigen receptors (CAR-T). The antitumor efficacy of bispecific anti-CD19 × anti-CD3 (CD19×CD3) T cell engager (BiTE)-secreting STAb-T cells has been demonstrated in several mouse models of B-cell acute leukemia. Here, we have investigated the spatial topology and downstream signaling of the artificial immunological synapses (IS) that are formed by CAR-T or STAb-T cells. Upon interaction with CD19-positive target cells, STAb-T cells form IS with structure and signal transduction, which more closely resemble those of physiological cognate IS, compared to IS formed by CAR-T cells expressing a second-generation CAR bearing the same CD19-single-chain variable fragment. Importantly, while CD3 is maintained at detectable levels on the surface of STAb-T cells, indicating sustained activation mediated by the secreted BiTE, the anti-CD19 CAR was rapidly downmodulated, which correlated with a more transient downstream signaling. Furthermore, CAR-T cells, but not STAb-T cells, provoke an acute loss of CD19 in target cells. Such differences might represent advantages of the STAb-T strategy over the CAR-T approach and should be carefully considered in order to develop more effective and safer treatments for hematological malignancies.

100 Deals associated with CD1a-STAb T cells(Onechain Immunotherapeutics)

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Preclinical	ES	OneChain Immunotherapeutics SLStartup	20 Jan 2023

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