Boletín informativo InvivoGen – enero de 2019
Immune Checkpoint Blockade
Durante la última década, la comprensión de los pasos clave en la regulación de las respuestas de las células T ha llevado al desarrollo de los puntos de control inmunitarios que bloquean los anticuerpos monoclonales (mAb) para combatir el cáncer. Los primeros mAbs aprobados por la FDA han proporcionado resultados sin precedentes en el melanoma y el cáncer de pulmón, aunque con una variación considerable en las tasas de respuesta (10% a 90%) y una toxicidad significativa1,2. Esta revolución en la terapia del cáncer es ahora la base para nuevas estrategias curativas.
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Immune Checkpoint Anti-human Antibodies
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T-cell responses first rely on the T-cell receptor (TCR) recognition of MHC:peptide complexes on antigen presenting cells (APCs). Further engagement of co-stimulatory and co-inhibitory molecules guarantees the onset and the limitation of T-cell activities. These molecules have rightfully been named “immune checkpoints” (ICs). Initial studies focused on relieving the immunosuppresive brake by the co-inhibitory CTLA-4 (cytotoxic T lymphocyte associated protein 4) and PD-1 (programmed cell death 1) receptors3. CTLA-4 is expressed by activated and regulatory T cells (Tregs), and exerts competitive binding for stimulatory CD28 ligands (CD80/CD86). PD-1 is expressed by activated and exhausted T cells, and binding to its ligands PD-L1 and PDL-2 directly inhibits TCR signaling through SHP2-mediated dephosphorylation of proximal signaling elements3. Of note, recent findings point CD28 as a convergent regulation target for both CTLA-4 and PD-1, and call attention to the regulation of intra-tumoral T-cell trafficking by PD-13.
Therapeutic IC-blocking mAbs have a dual activity inherent to their structure: while the variable regions bind to IC-epitopes, the “fragment crystallizable” (Fc) mediates targeted cell death through selective interaction with the complement molecule C1q (CDC: complement dependent cytotoxicity) and the Fc receptors on innate effector cells (ADCC: antibody dependent cellular cytotoxicity, ADCP: antibody dependent cellular phagocytosis)4. To date, approved IC-mAbs are IgG1s and IgG4s depending on the necessity to protect or kill the target cells5. Anti-CTLA4 ipilimumab and anti-PDL1 atezolizumab are IgG1s that are expected to cause preferential Treg and tumor cell depletion, respectively1,3. On the contrary, anti-PD1 nivolumab & pembrolizumab are modified IgG4s with low effector functions, mainly operating through blocking PD-1 interaction with its ligands1,5. Altogether, these IC-mAbs allow better activation of effector T cells, and the combination of anti-CTLA4 and anti-PD1/PDL1 improves survival1,3.
The challenge of IC immunotherapy is to improve the mAb response rates in a larger panel of cancers. A first approach is to modulate mAbs’ functionality through Fc engineering6 (see next page). For example, atezolizumab is a non-glycosylated IgG1 that retains its blocking activity but lacks cytotoxic functions3. New anti-CLTA4 mAbs with increased or dampened effector functions have also been developed and are under clinical trials1. Other strategies targeting more co-inhibitory molecules on T cells (e.g. LAG3, TIM-3, TIGIT, VISTA) have entered clinical trials, even though their biological roles is not fully understood3,7. The next generation of therapeutic mAbs also includes agonist agents targeting co-stimulatory molecules (OX40, ICOS, GITR, 4-1BB, CD40) on T cells to potentiate effector responses3,7. Importantly, combination of the above-mentioned approaches hold important promises7.
The future of anti-tumor immunotherapy relies on the induction of responses at multiple levels, including harnessing of other effector cells (e.g. natural killers, neutrophils) in addition to T cells. As an example, anti-NKG2A monalizumab blocks inhibitory signaling in natural killer cells and subsets of cytotoxic T cells, and further potentiates other therapeutic mAbs8. The identification of reliable predictive biomarkers and the combination of IC-therapies with other immunotherapies (e.g. adoptive T cell-therapy, oncolytic viruses, agonists for pattern recognition receptors), and radio/chemotherapies, may lead to the ultimate maximization of response rates9.
1. Kavecansky J and Pavlick A.C. 2017. Beyond checkpoint inhibitors: the next generation of immunotherapy in oncology. AJHO. 13(2):9.
2. Ribas A. and Wolchock J.D. 2018. Cancer immunotherapy using checkpoint blockade. Science. 359:1350.
3. Wei, S.C. et al. 2018. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8(9):1069.
4. Quast I. et al. 2017. Regulation af antibody effector functions through IgG Fc N-glycosylation. Cell. Mol. Life. Sci. 74(5):837.
5. Almagro, J.C. et al. 2018. Progress and challenges in the design and clinical development of antibodies for cancer therapy. Front. Immunol. 8:1751.
6. Whang, X. et al. 2018. IgG Fc engineering to modulate antibody effector functions. Protein Cell. 9:63.
7. Donini, C. et al. 2018. Next generation immune-checkpoints for cancer therapy. J Thorac Dis. 10 (suppl 13): S1581.
8. André P. et al. 2018. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 175:1731.
9. Marshall H.T. and Djamgoz B.A. 2018. Immuno-oncology: emerging targets and combination therapies. Front. Oncol. 8:315.