When Engineering Meets Immunology Engineered Immune Cells for Cancer Therapy : Current Status and Prospects Yong Taik Lim, Ph.D. Nanomedical Systems Laboratory (http://www.nanomedicalsystems.org) SKKU Advanced Institute of Nanotechnology/School of Chemical Engineering Sungkyunkwan University
Technology Developments for Cancer Therapy Surgery Chemotherapy / radiotherapy Bone marrow transplantation Immunomodulators Cell signaling / angiogenesis modulators Gene therapy Stem cell and Immune cell therapy c.1930s c.1950s c.1970s c.1980s c.1990s c.2000s
Nanomaterials Applied to Cancer Immunotherapy Key features of their size, shape and surface molecule organization. can be used to induce innate immune responses that promote adaptive immunity.
Immunostimulants : Potential Targets for Enhanced Immunity
Nanoparticles Reshapes the Induction of Immune Response
Challenging Issue I : Targeted Delivery
Nanotechnology for Cell-based Cancer Vaccine (1)
Nanotechnology for Cell-based Cancer Vaccine (2)
Immunosuppressive networks and checkpoints controlling antitumor immunity
Nanotechnology for Cancer Immunotherapy (3)
FDA-approved Cancer Immunotherapy Table 1 Immunotherapies with FDA-approval for cancer treatment Agent Class Indication FDA Ipilimumab Anti-CTLA-4-blocking mab Metastatic melanoma Reference ID: 3417,736 Nivolumab Anti-PD-1-blocking mab Metastatic melanoma, squamous lung cancer (2 nd line) Reference ID: 3677,021 Pembrolizumab Anti-PD-1-blocking mab Metastatic melanoma Reference ID: 3621,876 Sipuleucel (Provenge) Cell-based vaccine Castration resistant metastatic prostate cancer SR-1346.02, 28 SEP 2009 High dose IL-2 Cytokine Metastatic melanoma, metastatic renal cell cancer Reference ID: 3165,255 Abbreviations: CTLA-4, cytotoxic T-lymphocyte protein 4; mab, monoclonal antibody.
Tumor cells Dendritic Cells (DC) for Cancer Therapy Inactivated Dendritic cells Helper T cells B cells Tumorspecific Antibody Tumor-specific activation Cytotoxic T cells Activated Dendritic cells Natural Killer cells Immunity to Tumor Tumor cell Death
Where this technology is.. Limitation and Low Therapeutic Efficacy High cost ($120,000/treatment) : Separation of immune cells > Ex vivo maturation and activation > In vivo injection. Dependence of therapeutic efficiency on the ex vivo cell culture condition. Low migration capability of injected DCs (0.5-2.0% migration) FDA approved (2010) Nature Biotechnology (December, 2014) Nature (February, 2015)
Tumor DCs in Tumor microenvironment vs. In vitro sirna-based strategy Tumor Immature DC antigen
Programmed Nanoparticles for Enhanced DCs-based Antitumor Therapy Heo et al, Biomaterials, 35, 590-600
In vitro gene silencing and DC activation Pro-inflammatory Cytokines Antigen-specific T cell Activation
Tracking of in vivo DCs migration Immature DC treated PLGA (OVA/ICG) Mature DC treated PLGA (OVA/ICG) + PLGA (R837/STAT3 sirna) 24h 48h Color NIR
In vivo CTL response and Tumor Growth Inhibition
In Vivo Programming of Dendritic Cells Kim et al, Angew. Chem. Int. Ed. 51(38), 9670-9673
QDs-STAT3 encapsulated PLGA Nanoparticles QDs-CpG ODN encapsulated PLGA Nanoparticles QDs-CpG ODN - STAT3 sirna encapsulated PLGA Nanoparticles Schematic illustration for the chemical synthesis of PLGA nanoparticles containin g QDs that were conjugated with CpG ODN and CpG-STAT3 sirna.
In vitro Gene Silencing Effect
Tracking of in vivo DCs migration a) 24h 48h 72h High Tumor Lymph node b) PBS HNC c) Low High Low
In vivo Gene Silencing and Tumor Growth Inhibition Tumor volume(mm 3 ) PBS CpG HNC STAT3 sirna CpG- STAT3 sirna TNF-α PBS CpG HNC STAT3 sirna CpG- STAT3 sirna STAT3 GAPDH IL-6 IL-12 GAPDH 1800 1500 1200 900 PBS CpG STAT3 sirna CpG-STAT3 sirna PBS STAT3 sirna 600 300 * CpG CpG-STAT3 sirna 0 0 8 12 16 20 Time (Days) Kim et al, Angew. Chem. Int. Ed. 51(38), 9670-9673
Pathogen-mimicking Multivalent Polymer Nanocomplex for Enhanced Immune Response Display of multivalent epitope
Enhanced Anti-tumor and Systemic Memory Response Kim et al, Angew. Chem. Int. Ed. 54(28), 8139-43
Combination Therapy : Immunotherapy + Chemotherapy TLR7(R837) + Anti-tumor drug (Paclitaxel) Biomaterials (2014) 35, 7998001
Prospects: Immunoengineering Can Enhance Cancer Immunotherapy Nanotechnology and Biomaterials can enhance the efficacy of immunostimulatory small molecules and biologics by altering their co-localization, biodistribution, and release kinetics Challengingly, tumors can evade immune surveillance. Consequently, most immunotherapies, particularly those directed against solid tumors, have thus far benefited only a minority of patients For this reason, facilitating antitumor immune cells to overcome the activation energy barrier presented by the immunosuppressive tumor microenvironment is an area of active investigation. Therefore, combination approaches that specifically inhibit tumor-associated Treg and innate suppressor cells with concomitant enhancement of antitumor effector immune responses have considerable potential as safe and effective cancer immunotherapeutics and vaccines of the future.
Immunotherapy of Hepatocellular Carcinoma Nature Reviews Gastroenterology & Hepatology (2015)
Critical Variables in Combining Targeted Agents with Immunotherapy