Rafael Blan­co Domínguez

Delta One T cells in can­cer immunotherapy

Abstract

Adop­tive cell ther­a­py has become a major avenue for can­cer treat­ment. While already imple­ment­ed as an autol­o­gous ther­a­py for B‑cell malig­nan­cies, next-gen­er­a­tion ther­a­pies aim for “off-the-shelf” allo­gene­ic prod­ucts that may be safe and effi­ca­cious in oth­er can­cer types includ­ing sol­id tumors. By virtue of being MHC/H­LA-inde­pen­dent and broad­ly reac­tive to many tumors (while spar­ing healthy cells), gd T cells are ide­al­ly placed to meet these goals. Crit­i­cal­ly, we have devel­oped a clin­i­cal-grade pro­to­col for expan­sion and dif­fer­en­ti­a­tion of cyto­tox­ic Vd1⁺ gd T cells, termed “Delta One T” (DOT) cells, and char­ac­ter­ized their anti-tumor prop­er­ties on the path to ther­a­peu­tic appli­ca­tion. Here we will dis­cuss the pre-clin­i­cal data that led to an ongo­ing Phase 1 clin­i­cal tri­al with DOT cells in Acute Myeloid Leukemia (AML) patients. We have pro­vid­ed in vivo proof-of-prin­ci­ple data for DOT cells in patient-derived xenograft AML mod­els; and dis­sect­ed the mol­e­c­u­lar mech­a­nisms of AML tar­get­ing by DOT cells. More­over, using a CD123-direct­ed Chimeric Anti­gen Recep­tor (CAR123), we have enhanced the intrin­sic capac­i­ty of DOT cells to elim­i­nate AML in vit­ro and in vivo. 

Expand­ing beyond hema­to­log­i­cal malig­nan­cies, the nat­ur­al tro­pism of Vδ1+ γδ T cells towards mucos­al tis­sues and their abil­i­ty to infil­trate tumor sites posi­tion DOT cells as promis­ing can­di­dates for explo­ration in sol­id tumors. Notably, we have demon­strat­ed the effi­ca­cy of DOT cells in tar­get­ing col­orec­tal can­cer (CRC), a par­tic­u­lar­ly chal­leng­ing can­cer type with lim­it­ed response to cur­rent immunother­a­pies. Uti­liz­ing com­bi­na­to­r­i­al approach­es, includ­ing in vit­ro cyto­tox­ic assays and ortho­topic xenograft murine mod­els, we have unveiled the mech­a­nisms gov­ern­ing tumor infil­tra­tion, recog­ni­tion, and response of DOT cells to the tumor microen­vi­ron­ment. Last, we will dis­cuss ways to improve their tumo­ri­ci­dal func­tion through either enhance­ment of cyto­tox­ic recep­tors or block­ade of inhibito­ry recep­tors. Over­all, our find­ings sup­port the clin­i­cal trans­la­tion of DOT-based cel­lu­lar prod­ucts as next-gen­er­a­tion allo­gene­ic can­cer ther­a­pies and under­score avenues for enhanc­ing their efficacy. 

Biography/​Link

In 2022, he com­plet­ed his PhD at the Span­ish Nation­al Cen­ter for Car­dio­vas­cu­lar Research (CNIC — Madrid, Spain) and the Uni­ver­si­dad Autóno­ma de Madrid in the field of car­dio-immunol­o­gy under the men­tor­ship of Prof. Pilar Mar­tin. Dur­ing this peri­od, he con­duct­ed trans­la­tion­al research from pre-clin­i­cal mod­els to clin­i­cal stud­ies, lead­ing to the iden­ti­fi­ca­tion of sig­nif­i­cant T cell-derived reg­u­la­to­ry mol­e­cules in car­dio­vas­cu­lar dis­eases. His find­ings were pub­lished in pres­ti­gious jour­nals and led to patent devel­op­ments, result­ing in mul­ti­ple awards, includ­ing the ESC Young Inves­ti­ga­tor Award (2021), the Mar­gari­ta Salas Award (2022), the Enrique Fuentes Quin­tana Award (2023), and the Pre­mio Extra­or­di­nario UAM (2023).

Notable achieve­ments include the dis­cov­ery of a Th17-derived myocardi­tis bio­mark­er (Blan­co-Dominguez et al., New Eng­land Jour­nal of Med­i­cine 2021) and a pop­u­la­tion of anti-inflam­ma­to­ry Treg cells in the infarct­ed heart impor­tant to pre­vent heart fail­ure devel­op­ment (Blan­co-Dominguez et al., Jour­nal of Clin­i­cal Inves­ti­ga­tions 2022). Research stays at La Jol­la Insti­tute for Immunol­o­gy (CA, USA) and the Mass­a­chu­setts Gen­er­al Hos­pi­tal (MA, USA) sig­nif­i­cant­ly con­tributed to the achieve­ments of his PhD work.

Recent­ly, he secured an EMBO post-doc­tor­al fel­low­ship to join Prof. Bruno Sil­va-San­tos’s team at the Insti­tu­to de Med­i­c­i­na Mol­e­c­u­lar (iMM — Lis­bon, Por­tu­gal), where he has been work­ing since 2022. His cur­rent focus lies in under­stand­ing the reg­u­la­tion of γδ T cells in the sup­pres­sive tumor microen­vi­ron­ment and expand­ing the appli­ca­tion of a γδ T cell-derived immunother­a­py, termed Delta One T cell, for sol­id tumors. Through ongo­ing col­lab­o­ra­tion with phar­ma­ceu­ti­cal com­pa­nies his work feeds direct­ly into the devel­op­ment of this adop­tive cell therapy.