Hele­na Florindo

Unveil­ing Sol­id TUmor Microen­vi­ron­ment for rev­o­lu­tion­ary nano-immunotherapies

Abstract

Among immunother­a­peu­tic approach­es, immune check­point inhibitors (ICI), have rev­o­lu­tion­ized the treat­ment of sev­er­al can­cers. How­ev­er, lim­it­ed effi­ca­cy has been obtained for can­cer vac­cines and severe immune-medi­at­ed side effects have been relat­ed to ICI under clin­i­cal devel­op­ment [1]. Look­ing into sol­id tumors, such as breast can­cer, pan­cre­at­ic can­cer, and melanoma, the high­ly immuno­sup­pres­sive tumor microen­vi­ron­ment (TME), and the immune eva­sion mech­a­nisms have lim­it­ed the infil­tra­tion by immune cells and ther­a­peu­tics [2]. Here we show the syn­er­gis­tic ther­a­peu­tic effect of nanomed­i­cines [3] in com­bi­na­tion with ICI in pre­clin­i­cal mod­els of breast car­ci­no­ma (BC), pan­cre­at­ic duc­tal ade­no­car­ci­no­ma (PDAC), and melanoma.

Poly­mer­ic nanopar­ti­cles (NP) were designed to tar­get den­drit­ic cells (DC) and the TME by incor­po­rat­ing tumor-asso­ci­at­ed anti­gens, toll-like recep­tor lig­ands CpG and Poly(I:C), and reg­u­la­tors of potent immune sup­pres­sor mol­e­cules with­in the TME. NP sur­face was mod­i­fied to pro­mote DC acti­va­tion, but also to poten­ti­ate their deliv­ery to the TME. Cy5.5‑labeled NP were exten­sive­ly inter­nal­ized by DC and trig­gered their acti­va­tion in vivo. High­er lev­els of DC-relat­ed co-stim­u­la­to­ry mol­e­cules such as CD80, CD86, and CD40, were observed when com­pared with non-car­bo­hy­drate car­ri­ers. The anti-tumor immune-medi­at­ed effect was eval­u­at­ed ex vivo in patient-derived organoids and in vivo in melanoma/P­DAC//BC-bear­ing mouse mod­els. NP suc­cess­ful­ly induced a potent immune-medi­at­ed anti-tumor response against melanoma, PDAC, and BC. Syn­er­gis­tic anti-tumor effects were observed when NP was com­bined with ICI. The mul­ti­func­tion­al nanomed­i­cines re-shaped the immune pro­fil­ing with­in the TME of melanoma, PDAC, and BC, which cor­re­lat­ed with the over­all anti-tumor effect obtained in this com­bi­na­to­r­i­al scheme. In par­tic­u­lar, 4T1 and E0771 tumor-bear­ing ani­mals treat­ed with the mul­ti­func­tion­al nanomed­i­cine com­bined with αOX40 showed a note­wor­thy tumor remis­sion, with pro­longed over­all survival.

In con­clu­sion, the devel­oped nan­otech­nol­o­gy-based sys­tem induced a strong anti­gen-spe­cif­ic immune response and unlocked melanoma, PDAC, and BC to stan­dard immunother­a­peu­tic approach­es, as immune check­point modulators.

Ref­er­ences

1. K. Hiam-Galvez K, et al. Nat Rev Can­cer 2021, 21, 345.
2. M. A. Mintz, J.G. Cys­ter. Immunol Rev 2020, 296, 48.
3. J. Con­niot et al. Nat Nan­otech 2019, 2, 105.

Biography/​Link

Hele­na Florindo grad­u­at­ed in Phar­ma­ceu­ti­cal Sci­ences in 2003 (Uni­ver­si­ty of Lis­bon) and obtained her Ph.D. degree in Phar­ma­ceu­ti­cal Tech­nol­o­gy in 2008 (Uni­ver­si­ty of Lis­bon), in col­lab­o­ra­tion with the Uni­ver­si­ty of London.

Cur­rent­ly, she is a Full Pro­fes­sor in the Depart­ment of Phar­ma­cy, Phar­ma­col­o­gy, and Health Tech­nolo­gies at the Fac­ul­ty of Phar­ma­cy, Uni­ver­si­ty of Lis­bon. Since 2015, she has been the head of the Bio­NanoSciences – Drug Deliv­ery & Immu­no­engi­neer­ing Research Group, at the Research Insti­tute for Med­i­cines (iMed.ULisboa), Uni­ver­si­ty of Lisbon.

Hele­na is also a mem­ber of the Por­tuguese Med­i­cines Agency Eval­u­a­tion Board (INFARMED) and an expert to the Euro­pean Med­i­cines Agency (EMA), thus sup­port­ing the eval­u­a­tion of mar­ket­ing autho­riza­tion pro­ce­dures for new drugs and bio­log­ics. This knowl­edge in reg­u­la­to­ry sci­ences also guides the research with­in her research group, which has been moti­vat­ed by the immune-oncol­o­gy field toward the ratio­nal devel­op­ment of func­tion­al­ized nanobio­ma­te­ri­als as nov­el immunother­a­pies for can­cer treat­ment. It includes the char­ac­ter­i­za­tion of the anti-tumor effects induced by the com­bi­na­tion of nano-vac­cines with nano-ther­a­peu­tics designed to mod­u­late the func­tions of key cells with­in the tumor microen­vi­ron­ment, such as T cells, myeloid-derived cells, and tumor cells.

Her major top­ics of research are:

1. Reg­u­la­tion of immu­ni­ty by tar­get­ing den­drit­ic cells (DC) using nan­otech­nol­o­gy-based tools to com­bine the anti­gen-car­ry capac­i­ty of nanopar­ti­cles (NP) and the spe­cif­ic tar­get­ing and mat­u­ra­tion of DC recep­tors in vivo. It aims to i) enhance anti­gen deliv­ery to DC; ii) mod­u­late anti­gen intra­cel­lu­lar pro­cess­ing and pre­sen­ta­tion path­ways; and iii) block sig­nal­ing path­ways relat­ed to tumor eva­sion mechanisms.
2. Size-based tar­get­ing of lymph node-res­i­dent immune cells by NP to over­come major bar­ri­ers for vac­cine com­po­nents and immunotherapies.
3. Char­ac­ter­i­za­tion of bio-respon­sive mate­ri­als’ impact on ger­mi­nal cen­ter response to gen­er­al­ly improve vac­cine efficacy.
4. Dis­sect­ing tumor stro­mal and immune cell inter­play to guide the design of mul­ti-tar­get­ing nano-con­ju­gates as inno­v­a­tive immunother­a­peu­tic treat­ments against metasta­t­ic can­cer dis­eases. Our recent work is focused on the char­ac­ter­i­za­tion of the inter­play of immune cells-lym­phat­ic endothe­lial cells-tumor cells, espe­cial­ly in the brain, which knowl­edge we are using to tai­lor nano-ther­a­peu­tic development.

Hele­na Florindo