Dmitriy Zamarin and Jedd D. Wolchok
Adoptive Cell Therapy (ACT)
• Mechanism: Direct killing of tumor cells/infected cells by specific lymphocytes
• Donor lymphocyte infusion (DLI): HLA-matched lymphocytes, used for tx of relapse after allogeneic SCT for CML & AML, & to lesser degree ALL. EBV-specific lymphocytes used for EBV-associated PTLD refractory to rituximab
• Tumor infiltrating lymphocytes (TIL): Lymphocytes isolated from tumors, cultured & expanded in vitro, & infused back into pt, typically preceded by lymphodepletion w/TBI or chemotherapy (NEJM1988;319:1676, J Clin Oncol2008;26:5233)
• Genetically modified lymphocytes
Chimeric antigen receptor (CAR): Autologous lymphocytes engineered to express non–MHC-restricted Ag recognition using Ag-specific monoclonal Ab variable regions fused w/TCR & costimulatory receptor domains (eg, CD28) in one molecule (PNAS 1993;90:720)
Engineered TCR: Autologous lymphocytes engineered to express MHC-restricted tumor-specific TCR (Science 2006;314:126)
• Mechanism: Induce tumor-specific immune response
• Whole cell vaccines: Autologous vs. allogeneic tumor lysates
• Modified whole cell vaccines: Tumor cells engineered to express immunostimulatory molecules like GM-CSF (GVAX)
• Protein vaccines: Full-length proteins, not restricted to specific HLA types. Use of CA testis Ag is a popular choice due to their lack of expression on nl adult tissues (eg, MAGE-A3/AS15, NY-ESO1)
• Peptide vaccines: Easier preparation than whole protein, but typically HLA-restricted (most commonly HLA-A2). Peptides can be from CA-testis Ag & tumor-specific Ag (eg, viral, mutated proteins)
• DNA vaccines: Instead of a protein, a DNA vector encoding an Ag of interest is used
• Dendritic cell (DC) vaccines: Typically involve gen. of DC ex vivo, most commonly from monocytes by cx w/cytokine cocktails for DC maturation. DC’s are then loaded w/autologous/allogeneic tumor cell lysates or specific Ag & are infused back into the pt.
Sipuleucel T: PBMC activated w/recombinant fusion protein, PA2024 (prostatic acid phosphatase) fused to GM-CSF. PBMC cell mixture contains DC precursors, T cells, B cells, & Mϕ in variable proportions. ↑ OS in met CRPC (NEJM 2010;363:411).
• Vectored vaccines: Ag of interest are introduced w/a recombinant viral vector (eg, vaccinia, adenovirus)
Prostvac-VF: Vaccine formulation of two recombinant vaccinia viral vectors, each encoding transgenes for PSA, & three immune costimulatory molecules (B7.1, ICAM-1, & LFA-3). ↑ OS in men w/met CRPC in Phase II studies (J Clin Oncol 2010;28:1099).
Oncolytic Viruses (OV)
• Mechanism: Induce preferential killing of tumor cells in conjunction w/immune stimulation to induce systemic antitumor immunity
• Oncovex GM-CSF: Modified GM-CSF-expressing HSV type 1 (HSV-1) (J Clin Oncol 2009;27:5763)
• Reolysin: Type III naturally occurring reovirus, selectively replicates in tumors w/activated Ras pathway (Clin Cancer Res 2010;16:3067)
• JX-594: Attenuated vaccinia virus expressing GM-CSF that selectively replicates in tumors w/activated EGFR-Ras pathway (Nature 2011;477:99)
• Other viruses in development: Measles virus, NDV, adenovirus, Coxsackie virus A21, Parvovirus, Poliovirus, Seneca Valley virus, retroviruses, vaccinia, HSV-1, VSV
Other Immunotherapeutic Targets & Strategies
• Treg: Suppress immune responses by the CD4 effector & CD8 cells. ↑ peripheral & tumor-infiltrating Tregs a/w worse outcomes in the majority of CAs
Targeting strategies: Anti-CD25 Ab (daclizumab), denileukin diftitox: Target CD25 (IL-2R) upregulated on the surface of Treg.
• Indoleamine 2,3-dioxygenase (IDO): Tryptophan-metabolizing enzyme upregulated in various tumor cells, DC, & cells of myeloid lineage. ↑ IDO leads to suppression of immune response & tolerance.
Targeting strategies: Small-molecule inhibitors targeting IDO
• Myeloid-derived suppressor cells (MDSC): Present w/in local tumor microenvironment & systemically & suppress immune responses by the CD4 effector & CD8 cells
Targeting strategies: ATRA, selective chemotherapy agents, PDE-5 inhibition (sildenafil), sunitinib, vitamin D3