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S. Albelda
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MS 04 - Harnessing the Full Potential of the Immune System (ID 22)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:C. Butts, P. Forde
- Coordinates: 9/07/2015, 14:15 - 15:45, Four Seasons Ballroom F3+F4
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MS04.04 - Microenvironment as a Target (ID 1863)
15:20 - 15:40 | Author(s): S. Albelda
- Abstract
- Presentation
Abstract:
The traditional approaches to lung cancer therapy have focused on treating the malignant epithelial cancer cells within the tumor. However, it is now realized that in most cases, most of the tumor consists of “supporting cells” that include endothelium, pericytes, fibroblasts, and a variety of innate and acquired (B cells and T cells) immune cells. Thus, targeting these non-tumor cells could be an alternative therapeutic strategy. This concept is already being used in clinical practice. One example is targeting the endothelial cells within the tumor using an anti-VEGF antibody (bevacizumab). Another example are the checkpoint inhibitors (anti-CTLA4 and anti-PD1 antibodies) that target endogenous T cells. However, it may also be possible to attack other targets such as macrophages, Tregs, neutrophils or cancer-associated fibroblasts (CAFs). Tumor-associated macrophages represent one target. These cells take on a tumor-supportive phenotype and produce anti-inflammatory cytokines/chemokines (i.e. TGFbeta, PGE2, IL10, VEGF), arginase (which inactivates T cells), and angiogenic factors. This has led to the hypothesis that changing the state of the macrophage to an anti-tumor phenotype in which immune-activating mediators would be made and antigen-presentation could be enhanced would have direct anti-tumor activities and would allow endogenous T cells to kill tumor cells. Macrophage activation has been attempted for many years using agents such as bacterial endotoxin, TNF, liposomal-encapsulated muramyl tripeptides, lipopeptides or oligonucleotides/agents that activate toll-like receptors. To date, however, this approach has not been very successful, primarily due to lack of specificity for tumor infiltrating macrophages resulting in intolerable systemic toxicity. Our group explored the use of a cell permeable flavonoid compound called DMXAA for this purpose. Administration of DMXAA causes activation of tumor-associated macrophages via multiple pathways with release of cytokines and chemokines resulting in hemorrhagic tumor necrosis, a subsequent inflammatory/immuno-permissive tumor environment, and ultimately attracts CD8 T cells into tumors (Jassar et al. 2005). Although intra-tumoral treatment of both large and small lung cancers in mouse models led to striking tumor regression, there was a major problem in translating this work- DMXAA does not react with human macrophages. Since we did not know how DMXAA was working (i.e. what was the DMXAA receptor that triggered macrophage activation) progress was stalled. This changed recently, when it was discovered that DMXAA worked by binding to a newly described intracellular sensor of cytosolic DNA (working through binding to cyclic dinucleotides) called STING (stimulator of Interferon Genes). STING activates innate immunity by signaling through the TBK/IRF3 axis, NF-kB and STAT6 pathways. Interestingly, it was noted that DMXAA bound well to mouse STING but NOT to human STING (explaining its lack of efficacy in humans). A company (Aduro Biotech) has designed a compound that binds to human STING and thus activates human macrophages like DMXAA activates mouse macrophages. Their lead compound has strong in vivo anti-tumor activity (much like DMXAA) and clinical trials using intra-tumoral injections are about to start (Corrales et al., 2015). Another potential target in the tumor microenvironment is the cancer-associated fibroblasts (CAFs). Fibroblasts and their associated stroma promote tumor growth through multiple mechanisms, including suppression of anti-tumor immunity, supporting angiogenesis, as a depot for growth factors/ cytokines/chemokines, modulating the inflammatory response, and shielding the tumor from infiltrating cells. Our group at Penn has been developing genetically altered T cells that can be targeted to any expressed surface antigen by transducing autologous T cells with a chimeric antigen receptor (CAR). A CAR is composed of a single chain antibody fused to the cytoplasmic sequences from the CD3zeta chain and a co-activating receptor (41BB/CD137). This construct combines antibody specificity with the ability to activate the killing machinery of T cells. Our lead CAR T cell target is CD19 to treat B cell malignancies, however, we are also testing CARs targeted to mesothelin (mesothelioma, lung cancer, pancreas cancer, ovarian cancer) and other solid tumor cell targets. We hypothesized that we could use this approach to eliminate CAFs. To do so, we identified Fibroblast Activation Protein (FAP) as a target antigen for CAFs. In epithelial-derived tumors, FAP is selectively expressed by cancer-associated stromal cells It is highly expressed in the stroma of lung (and many other) cancers, but not in benign tumors or normal adult quiescent tissues (although it is upregulated in wounds and fibrotic tissues). We thus produced T cells expressing anti-mouse FAP CARs. The FAP CAR T cells selectively killed FAP-expressing cells. Immune-competent C57BL/6 mice bearing large established subcutaneous murine lung cancers and human A549 tumors in immune-deficient mice were treated. FAP-CAR T cells reduced the number of FAP+ cells, markedly reduced the amount of tumor matrix and limited tumor growth in all three lung cancer models (Wang et al., 2014; Lo et al., 2015). We hope to move this approach forward to clinical trials in lung cancer and mesothelioma. We will likely combine anti-fibroblast therapy with chemotherapy, vaccines, or other types of immunotherapy. In summary, a new therapeutic paradigm is now emerging based on therapy aimed at the non-malignant host cells, NOT directly targeting the cancer cells. Examples include antibodies targeting endothelial cells and checkpoint inhibitors that target T cells. An advantage of this approach is that stromal cells are more genetically stable compared with tumor cells and they are unlikely to lose their antigen(s) and become invisible to T cells. Another advantage is the same targets could be used in multiple tumors. Future applications will likely include activation or elimination of TAMS, targeting fibroblasts, and deletion of T-regulatory cells. References: Corrales L, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Reports 2015. 11:1-13. Jassar, A., et al. Activated Tumor-Associated Macrophages and CD8[+] T-cells are the Key Mediators of Anti-tumor Effects of the Vascular Disrupting Agent DMXAA in Murine Models of Lung Cancer and Mesothelioma”. Cancer Research 2005. 65:11752-11761. Lo A, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015 May 15. [Epub ahead of print] Wang LC, et al. Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity. Cancer Immunology Research 2014. 2:154-166.
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ORAL 28 - T Cell Therapy for Lung Cancer (ID 132)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P.S. Adusumilli, E. Smit
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL28.01 - Checkpoint Blockade Augments TCR Engineered Adoptive T Cell Therapy for Lung Cancer (ID 344)
16:45 - 16:56 | Author(s): S. Albelda
- Abstract
Background:
Adoptive T-cell immunotherapy (ACT) has shown great promise in melanoma and hematologic malignancies; however one major limitation of engineered T cells targeting solid tumors is likely to be tumor microenvironment-induced hypofunction of the T cells. To study and limit this problem, we have developed a model in which human T cells engineered to target the antigen NYESO1 using a high-affinity engineered TCR (Ly95) are injected into mice bearing human A549 lung cancer cells. Using this model we demonstrate upregulation of PD1 and TIM3 on Ly95 TILs. We were able to augment T cell anti-tumor activity by combining Ly95 T cell therapy with anti-hPD1 and anti-hTIM3 antibodies.
Methods:
In vitro: Human T cells activated by anti-CD3/CD28 Dynabeads and transduced with lentivirus had 50% expression of Ly95 TCR as measured by flow cytometry. They were cocultured with marked tumor cells to measure IFNg release and antigen-specific killing. In vivo: Immunodeficient mice with 200mm[3] flank A549-A2-ESO (AAE) tumors received 10[7] T cells via tail vein. Three weeks later, tumors were harvested/digested, and human TILs were isolated/assesssed for tumor killing/IFNg secretion. This was repeated after the TILs were rested for 24hrs at 37[0]C/5%CO2. The number of TILs and PD1/TIM3 expression on the isolated TILs were assessed by flow cytometry at fresh harvest and post rest. The in vivo experiment was repeated comparing Ly95 T cells alone vs. Ly95 T cells plus either/both intraperitoneal (IP) anti-hPD1 or/and IP anti-hTIM3 at 10mg/kg every 5 days.
Results:
Ly95 TCR T cells were able to kill AAE tumor cells and secrete high amounts of IFNg in an antigen-specific/dose dependent fashion after 18hr coculture. 10[7 ]IV Ly95 T cells were able to slow AAE flank tumor growth as compared to control tumors (498mm[3 ]vs. 1009mm[3], p<0.05.) Flow cytometric analysis of harvested/digested tumors revealed that 5.2% of the tumor digest was human TILs. Freshly isolated TILs were hypofunctional in their ability to kill tumor cells and release IFNg when compared to cryopreserved Ly95 T cells (p<0.05.) After overnight rest away from tumor, TILs improved in function. Further analysis revealed that Ly95 TILs had upregulated their expression of PD1 and TIM3 (increase from 5 to 40% in PD1 and from 17 to 50% in TIM3.) Combining a single Ly95 T cell IV injection with multiple IP anti-hPD1 and anti-hTIM3 injections resulted in 43% reduction in flank tumor size compared to Ly95 T cell injection alone (189mm[3] vs. 332mm[3], p<0.05.)
Conclusion:
The PD1 and TIM3 pathways are involved in tumor-induced hypofunction of TCR engineered TILs. Combining anti-hPD1 and anti-hTIM3 antibodies with TCR T cells, and likely CAR T cells, will likely enhance the efficacy of these approaches in lung cancer and other solid tumors.
