Abstract B028: Blockade of the CD47 “Do not eat” signal by TTI-621 (SIRPαFc) leads to enhanced antitumor CD8+ T cell responses in vitro
Bibliographic record
Abstract
Abstract High expression of the CD47 “do-not-eat” signal is a mechanism commonly used by tumor cells to escape phagocytosis by macrophages. CD47 transmits an inhibitory signal upon binding to its receptor signal-regulatory protein α (SIRPα) on the surface of macrophages. We have previously shown that TTI-621, a soluble SIRPαFc fusion protein, neutralizes the suppressive effects of CD47 and triggers macrophage-mediated phagocytosis of tumor cells in vitro, and effectively controls tumor growth in vivo. Using a human culture system, we investigated whether this increase in macrophage-mediated phagocytosis results in augmented T cell responses. To evaluate the T cell response to a model tumor antigen, Jurkat, a human leukemia cell line, was stably transfected with a construct containing the human cytomegalovirus phosphoprotein pp65 (CMV-Jurkat). Consistent with our previous studies, blockade of CD47 on CMV-Jurkat cells using TTI-621 led to a dramatic increase in tumor cell phagocytosis by primary macrophages derived from peripheral blood monocytes of healthy, HLA-A2+ donors. Using a high-affinity soluble TCR multimer that specifically recognizes an immunodominant epitope from pp65 complexed with HLA-A2, we found that TTI-621-mediated phagocytosis of CMV-Jurkat resulted in increased pp65 antigen presentation on the surface of macrophages. In cultures treated with a control Fc fragment, where macrophages only exhibited a low level of phagocytosis, no presentation of pp65 peptide could be detected. Moreover, mock-transfected tumor cells were efficiently phagocytosed in the presence of TTI-621, yet did not result in presentation of CMV pp65 peptide. To assess whether this increase in antigen presentation results in augmented T cell responses, macrophages from the phagocytosis assay were co-cultured with autologous CD8+ T cells for five days. We observed robust proliferation of CMV pp65-specific CD8+ T cells following co-culture with macrophages that had phagocytosed CMV-Jurkat in the presence of TTI-621 compared to control Fc treatment. In contrast, no proliferation of CMV pp65-specific CD8+ T cells occurred when macrophages had phagocytosed mock-transfected tumor cells, suggesting that the proliferation of CMV-specific CD8+ T cells is a tumor antigen-specific response. In addition, preliminary data indicate that primed CMV-specific CD8+ T cells are fully functional and are capable of exhibiting cytotoxicity against CMV-Jurkat. Collectively, our study demonstrates for the first time that in a human culture system, blockade of the CD47 “do not eat” signal results in increased phagocytosis, augmented tumor antigen presentation and enhanced anti-tumor CD8+ T cell responses. These results provide further support for the concept that CD47 lies at the intersection of the innate and adaptive immune systems. TTI-621, which is currently in a Phase I trial in patients with advanced hematological malignancies (NCT02663518), may thus be able to harness the anti-tumor activity of both macrophages and T cells. Citation Format: Natasja Nielsen Viller, Tran Truong, Emma Linderoth, Lisa D. Johnson, Stephane Viau, Gloria H. Y. Lin, Mark Wong, Xinli Pang, Penka S. Petrova, Robert A. Uger. Blockade of the CD47 “Do not eat” signal by TTI-621 (SIRPαFc) leads to enhanced antitumor CD8+ T cell responses in vitro [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B028.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".