scholarly journals Tumor masses support naive T cell infiltration, activation, and differentiation into effectors

2010 ◽  
Vol 207 (8) ◽  
pp. 1791-1804 ◽  
Author(s):  
Elizabeth D. Thompson ◽  
Hilda L. Enriquez ◽  
Yang-Xin Fu ◽  
Victor H. Engelhard
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration

Studies of T cell responses to tumors have focused on the draining lymph node (LN) as the site of activation. We examined the tumor mass as a potential site of activation after adoptive transfer of naive tumor-specific CD8 T cells. Activated CD8 T cells were present in tumors within 24 h of adoptive transfer and proliferation of these cells was also evident 4–5 d later in mice treated with FTY720 to prevent infiltration of cells activated in LNs. To confirm that activation of these T cells occurred in the tumor and not the tumor-draining LNs, we used mice lacking LNs. Activated and proliferating tumor-infiltrating lymphocytes were evident in these mice 24 h and 4 d after naive cell transfer. T cells activated within tumors acquired effector function that was evident both ex vivo and in vivo. Both cross-presenting antigen presenting cells within the tumor and tumor cells directly presenting antigen activated these functional CD8 effectors. We conclude that tumors support the infiltration, activation, and effector differentiation of naive CD8 T cells, despite the presence of immunosuppressive mechanisms. Thus, targeting of T cell activation to tumors may present a tool in the development of cancer immunotherapy.

A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Phase Ii Trial ◽  
Ex Vivo ◽  
Vaccine Strategy ◽  
Randomized Phase Ii

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

scholarly journals 702 TJ-CD4B (ABL111), a Claudin18.2-targeted 4-1BB tumor engager induces potent tumor-dependent immune response without dose-limiting toxicity in preclinical studies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A730-A730
Author(s):  
Wenqing Jiang ◽  
Zhengyi Wang ◽  
Zhen Sheng ◽  
Jaeho Jung ◽  
Taylor Guo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Gene Expression Analysis ◽  
Cell Activation ◽  
Clinical Development ◽  
Cynomolgus Monkeys ◽  
Anti Tumor Activity

Background4-1BB (CD137) is a co-stimulatory receptor that stimulates the function of multiple immune cells. Its ability to induce potent anti-tumor activity makes 4-1BB an attractive target for immuno-oncology. However, clinical development of a monospecific 4-1BB agonistic antibody has been hampered by dose-limiting hepatic toxicities. To minimize systemic toxicities, we have developed a novel Claudin18.2 (CLDN18.2) x 4-1BB bispecific antibody, TJ-CD4B (ABL111) that stimulates 4-1BB pathway only when it engages with Claudin 18.2, a tumor-associated antigen specifically expressed in gastrointestinal cancers. TJ-CD4B (ABL111) is now being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT04900818).MethodsTJ-CD4B (ABL111) was evaluated in vivo using the human 4-1BB knock-in mice bearing CLDN18.2 expressing MC38 tumor cells. Pharmacodynamic effects upon treatment were characterized in tumor tissue and blood. Immunophenotyping of the tumor microenvironment (TME) and peripheral blood was performed by flow cytometry. Soluble biomarkers were measured using Luminex-based multiplex assay. In-depth gene expression analysis was performed on primary human CD8+ T cells that were co-cultured with CLDN18.2 expressing cells in the presence of anti-CD3 using NanoString nCounter®. Pharmacokinetic (PK) and toxicity study were performed in cynomolgus monkeys.ResultsTJ-CD4B (ABL111) elicited complete tumor regression in 13 out of 18 MC38 tumor bearing mice given at a dose above 2 mg/kg. Dose-dependent anti-tumor activity was associated with enhanced T cell activation in TME and expansion of memory T cells in the peripheral blood. Increased CD8+ T cells number and proliferation were observed in both tumor nest and surrounding stroma while the level of soluble 4-1BB in the serum was also elevated in response to the treatment. In vitro gene expression analysis by Nanostring revealed TJ-CD4B(ABL111) effectively activated immune pathways characterized by IFN?-signaling and T cell inflammation. Preclinically, TJ-CD4B was well tolerated at the repeated doses up to 100 mg/kg/wk in cynomolgus monkeys without the adverse influence on the liver function which is generally affected by 4-1BB activation. Besides, no cytokine release or immune activation was observed in the periphery.ConclusionsTJ-CD4B (ABL111) is a novel CLDN18.2 dependent 4-1BB bispecific agonist antibody that induced T cell activation and memory response in tumor with CLDN18.2 expression, leading to a strong anti-tumor activity in vivo. TJ-CD4B did not induce systemic immune response nor hepatic toxicity due to the CLDN18.2 dependent 4-1BB stimulation. These data warrant the current clinical development in phase I trial to validate the safety properties and tumor specific responses.

scholarly journals A Critical Role for Cd40–Cd40 Ligand Interactions in Amplification of the Mucosal Cd8 T Cell Response

1999 ◽  
Vol 190 (9) ◽  
pp. 1275-1284 ◽  
Author(s):  
Leo Lefrançois ◽  
Sara Olson ◽  
David Masopust
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Interleukin 12 ◽  
Cd8 Cells

The role of CD40 ligand (CD40L) in CD8 T cell activation was assessed by tracking antigen-specific T cells in vivo using both adoptive transfer of T cell receptor transgenic T cells and major histocompatibility complex (MHC) class I tetramers. Soluble antigen immunization induced entry of CD8 cells into the intestinal mucosa and cytotoxic T lymphocyte (CTL) differentiation, whereas CD8 cells in secondary lymphoid tissue proliferated but were not cytolytic. Immunization concurrent with CD40L blockade or in the absence of CD40 demonstrated that accumulation of CD8 T cells in the mucosa was CD40L dependent. Furthermore, activation was mediated through CD40L expressed by the CD8 cells, since inhibition by anti-CD40L monoclonal antibodies occurred after adoptive transfer to CD40L-deficient mice. However, mucosal CD8 T cells in normal and CD40−/− mice were equivalent killers, indicating that CD40L was not required for CTL differentiation. Appearance of virus-specific mucosal, but not splenic, CD8 cells also relied heavily on CD40–CD40L interactions. The mucosal CTL response of transferred CD8 T cells was MHC class II and interleukin 12 independent. The results established a novel pathway of direct CD40L-mediated CD8 T cell activation.

scholarly journals Immunologic ignorance of vascular endothelial cells expressing minor histocompatibility antigen

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4588-4595 ◽  
Author(s):  
Beatrice Bolinger ◽  
Philippe Krebs ◽  
Yinghua Tian ◽  
Daniel Engeler ◽  
Elke Scandella ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Histocompatibility Antigen ◽  
Target Cells ◽  
Minor Histocompatibility Antigen

Abstract Endothelial cells (ECs) presenting minor histocompatibility antigen (mhAg) are major target cells for alloreactive effector CD8+ T cells during chronic transplant rejection and graft-versus-host disease (GVHD). The contribution of ECs to T-cell activation, however, is still a controversial issue. In this study, we have assessed the antigen-presenting capacity of ECs in vivo using a transgenic mouse model with beta-galactosidase (β-gal) expression confined to the vascular endothelium (Tie2-LacZ mice). In a GVHD-like setting with adoptive transfer of β-gal–specific T-cell receptor–transgenic T cells, β-gal expression by ECs was not sufficient to either activate or tolerize CD8+ T cells. Likewise, transplantation of fully vascularized heart or liver grafts from Tie2-LacZ mice into nontransgenic recipients did not suffice to activate β-gal–specific CD8+ T cells, indicating that CD8+ T-cell responses against mhAg cannot be initiated by ECs. Moreover, we could show that spontaneous activation of β-gal–specific CD8+ T cells in Tie2-LacZ mice was exclusively dependent on CD11c+ dendritic cells (DCs), demonstrating that mhAgs presented by ECs remain immunologically ignored unless presentation by DCs is granted.

scholarly journals Human Immunodeficiency Virus-Specific Circulating CD8 T Lymphocytes Have Down-Modulated CD3ζ and CD28, Key Signaling Molecules for T-Cell Activation

2000 ◽  
Vol 74 (16) ◽  
pp. 7320-7330 ◽  
Author(s):  
Linda A. Trimble ◽  
Premlata Shankar ◽  
Mark Patterson ◽  
Johanna P. Daily ◽  
Judy Lieberman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cd8 T Lymphocytes ◽  
Immunodeficiency Virus

ABSTRACT Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV-infected donors down-modulate CD3ζ, the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3ζ down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3ζ-down-modulated subset. HIV-specific CD8 T cells, identified by tetramer staining, are CD3ζ−. CD8 T cells with down-modulated CD3ζ also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (HLA-DR+ CD62L−). After T-cell activation, CD3ζ-down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor α-chain CD25 and produce gamma interferon but not IL-2. Therefore HIV-specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation. The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3ζ is not reexpressed even after IL-2 exposure.

scholarly journals HIV-specific CD8+ T-cells in tonsils express exhaustive TRM-like signatures

2021 ◽  
Author(s):  
Rabiah Fardoos ◽  
Sarah K. Nyquist ◽  
Osaretin E. Asowata ◽  
Samuel W. Kazer ◽  
Alveera Singh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Cytolytic Activity ◽  
Lymphoid Tissues ◽  
People Living With Hiv ◽  
Natural Immunity

Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRMs within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and transcriptionally TRM-like profile that is distinct from blood. In PLWH, CD8+ TRM-like cells are highly expanded and adopt a more cytolytic, activated and exhausted phenotype characterized by increased expression of CD69, PD-1 and perforin, but reduced CD127. This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood. Single-cell profiling of these cells revealed a clear transcriptional signature of T-cell activation, clonal expansion and exhaustion ex-vivo. In contrast, this signature was absent from HIV-specific CD8+ T-cells in tonsils isolated from a natural HIV controller, who expressed lower levels of cell surface PD-1 and CXCR5, and reduced transcriptional evidence of T-cell activation, exhaustion and cytolytic activity. Thus, we show that HIV-specific TRM-like CD8+ T-cells in tonsils from non-HIV controllers are enriched for activation and exhaustion profiles compared to those in blood, suggesting that lymphoid HIV specific CD8+ TRM cells are potentially ideal candidates for immunotherapy to modulate their ability to targeting the HIV reservoirs.

498 Downregulation of CD5 in CD8+ T tumour-infiltrating lymphocytes associates with increased level of activation and exhaustion

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A533-A533
Author(s):  
Faizah Alotaibi ◽  
Mark Vincent ◽  
Weiping Min ◽  
James Koropatnick
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
Tcr Signaling ◽  
Peripheral Organs ◽  
Infiltrating Lymphocytes

BackgroundCD5, a member of the scavenger receptor cysteine-rich superfamily, is a marker for T cells and a subset of B cells (B1a). CD5 associates with T-cell and B-cell receptors and impair TCR signaling1 2 and increased CD5 is an indication of B cell activation. Furthermore, CD5 levels on CD8+ T cell splenocytes were significantly increased after TCR/CD3 stimulation using ex vivo treatment with anti-CD3/anti-CD28 MAbs compared to non-stimulated CD8+ T splenocytes.3 Previous studies have shown a correlation between CD5 and anti-tumour immunity where CD5 knockout mice inoculated with B16F10 melanoma cells had delayed tumour growth compared to wild type mice.4 In tumour-infiltrating lymphocytes (TILs) isolated from lung cancer patients, CD5 levels were negatively correlated with anti-tumour activity and tumour-mediated activation-induced T cell death,5 suggesting that CD5 could impair activation of anti-tumour T cells. However, the correlation between CD5 level expression and T cell activation and exhaustion in the tumour microenvironment and in peripheral organs is ill-defined and requires further investigation.MethodsWe determined CD5 levels in T cell subsets in different organs in mice bearing syngeneic 4T1 breast tumour homografts and assessed the relationship between CD5 and increased CD69 and PD-1 (markers of T cell activation and exhaustion) by flow cytometry.ResultsWe report that T cell CD5 levels were higher in CD4+ T cells than in CD8+ T cells in 4T1 tumour-bearing mice, and that high CD5 levels on CD4+ T cells were maintained in peripheral organs (spleen and lymph nodes). However, both CD4+ and CD8+ T cells recruited to tumours had reduced CD5 compared to CD4+ and CD8+ T cells in peripheral organs. In addition, CD5highCD4+ T cells and CD5highCD8+ T cells from peripheral organs exhibited higher levels of activation and associated exhaustion compared to CD5lowCD4+ T cell and CD5lowCD8+ T cell from the same organs. Interestingly, CD8+ T cells among TILs and downregulated CD5 were activated to a higher level, with concomitantly increased exhaustion markers, than CD8+CD5+ TILs.ConclusionsThus, differential CD5 levels among T cells in tumours and lymphoid organs can be associated with different levels of T cell activation and exhaustion, suggesting that CD5 may be a therapeutic target for immunotherapeutic activation in cancer therapy.AcknowledgementsThe author thanks Rene Figueredo and Ronak Zareardalan for their assistance in animal workEthics ApprovalThis study was approved by the Animal Use Subcommittee of the University of Western OntarioReferencesAzzam HS, et al., Fine tuning of TCR signaling by CD5. The Journal of Immunology 2001. 166(9): p. 5464–5472.Voisinne GA, Gonzalez de Peredo and Roncagalli R. CD5, an undercover regulator of TCR signaling. Frontiers in Immunology 2018;9:p. 2900.Alotaibi, F., et al., CD5 blockade enhances ex vivo CD8+ T cell activation and tumour cell cytotoxicity. European journal of immunology 2020;50(5): p. 695–704.Tabbekh, M., et al., Rescue of tumor-infiltrating lymphocytes from activation-induced cell death enhances the antitumor CTL response in CD5-deficient mice. The Journal of Immunology, 2011. 187(1): p. 102–109.Dorothée, G., et al., In situ sensory adaptation of tumor-infiltrating T lymphocytes to peptide-MHC levels elicits strong antitumor reactivity. The Journal of Immunology 2005;174(11): p. 6888–6897.

scholarly journals Preclinical Evaluation of 89Zr-Df-IAB22M2C PET as an Imaging Biomarker for the Development of the GUCY2C-CD3 Bispecific PF-07062119 as a T Cell Engaging Therapy

2021 ◽  
Author(s):  
Kevin P. Maresca ◽  
Jianqing Chen ◽  
Divya Mathur ◽  
Anand Giddabasappa ◽  
Adam Root ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Standard Uptake Value ◽  
Imaging Biomarker ◽  
Distribution Analysis ◽  
T Cell Infiltration ◽  
Positron Emission

Abstract Purpose A sensitive and specific imaging biomarker to monitor immune activation and quantify pharmacodynamic responses would be useful for development of immunomodulating anti-cancer agents. PF-07062119 is a T cell engaging bispecific antibody that binds to CD3 and guanylyl cyclase C, a protein that is over-expressed by colorectal cancers. Here, we used 89Zr-Df-IAB22M2C (89Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89Zr-Df-IAB22M2C to track anti-tumor activity induced by PF-07062119 in a human CRC adoptive transfer mouse model (with injected activated/expanded human T cells), as well as the correlation of tumor radiotracer uptake with CD8+ immunohistochemical staining. Procedures NOD SCID gamma mice bearing human CRC LS1034 tumors were treated with four different doses of PF-07062119, or a non-targeted CD3 BsAb control, and imaged with 89Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89Zr-Df-IAB22M2C in tissues on days 4 and 9, with additional data collected on day 6 (supplementary). Data were analyzed and reported as standard uptake value and %ID/g for in vivo imaging and ex vivo tissue distribution. In addition, tumor tissues were evaluated by immunohistochemistry for CD8+ T cells. Results The results demonstrated substantial mean uptake of 89Zr-Df-IAB22M2C (%ID/g) in PF-07062119-treated tumors, with significant increases in comparison to non-targeted BsAb-treated controls, as well as PF-07062119 dose-dependent responses over time of treatment. A moderate correlation was observed between tumor tissue radioactivity uptake and CD8+ cell density, demonstrating the value of the imaging agent for non-invasive assessment of intra-tumoral CD8+ T cells and the mechanism of action for PF-07062119. Conclusion Immune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.

scholarly journals AMV564 Depletes Myeloid-Derived Suppressor Cells and Expands T Cells: Potential to Address Key Limitations of Cellular Therapies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1702-1702
Author(s):  
Sterling Eckard ◽  
Bianca Rojo ◽  
Victoria Smith ◽  
Patrick Chun
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
Target Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Car T

Abstract Background Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive tumor environment and are a barrier to immune therapeutic approaches, including cell-based therapies such as chimeric antigen receptor T cells (CAR T). Despite good overall response rates with certain subsets of B cell leukemias and lymphomas, a significant percentage of patients treated with CAR T therapy do not respond or subsequently relapse. Poor CAR T expansion, poor persistence of infused cells, and clinical treatment failure are associated with tumor and systemic immune dysregulation including high blood levels of peripheral blood monocytic MDSC (M-MDSCs) and interleukin-6, both of which are associated with lack of durable responses 1. In addition, CAR T therapy has been limited by the occurrence of severe cytokine release syndrome (CRS), which is associated with high IL-6 production 2 by myeloid cells such as MDSC. AMV564 is a potent T cell engager that selectively depletes MDSC while promoting T cell activation and proliferation without significant IL-6 induction 3. In phase 1 studies in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors, AMV564 has been demonstrated to be clinically safe and active with some patients achieving complete remissions. Methods Cell lines, primary human cells, and patient samples were analyzed using flow cytometry with appropriate marker panels. T cell activation and cytotoxicity assays were conducted using primary human T cells from healthy donors and target cells (3:1 ratio) for 72 hours. T cell activation using ImmunoCult Human CD3/CD28 served as an assay reference. Results Analysis of patients treated with AMV564 demonstrated statistically significant selective depletion of M-MDSC by cycle 2 (Fig. 1A). While on AMV564 therapy, median IL-6 levels remained below 100 pg/mL despite robust T cell activation and expansion. Granzyme B production by CD8 T cells increased significantly between Cycle 1 and Cycle 2 in patients on therapy, and effector CD8 T cells expand over the course of treatment (Fig. 1B-C). These data collectively support the finding that AMV564 both removes a key source of immune suppression and is a potent agonist of T cell function and differentiation in patients. AMV564 potently activates and expands primary T cells ex vivo. Across donors, peak proliferation was significantly higher with AMV564 than with the CD3/CD28 reference (Fig. 2A). Importantly, T cell viability remained significantly higher with AMV564 when compared to reference control (CD3/CD28), and there was no evidence of activation-induced cell death (AICD) in AMV564-treated samples (Fig. 2B). Conclusions AMV564 depletes MDSC and stimulates expansion and longevity of T cells without significant IL-6 induction, suggesting a possible strategy for improvement in efficacy of cell-based therapy such as CAR T approaches. As circulating M-MDSC both at baseline and after CAR T infusion correlate with poor clinical efficacy 4, AMV564 may have beneficial effects during the conditioning phase of cell therapy, after re-infusion of CAR T products into patients, or both. Ex vivo studies using donor T cells and ongoing in vitro studies using CAR T molecules suggest that AMV564 may provide dual benefit with respect to both depletion of MDSC and T cell agonism. References 1. Jain, et al; Blood 2021; 137 (19): 2621-2633. doi: https://doi.org/10.1182/blood.2020007445 2. Li et al., Sci. Transl. Med. 11, eaax8861 (2019) 3. Eckard et al; Cancer Res 2021; (81) (13 Supplement) 528; DOI: 10.1158/1538-7445.AM2021-528 4. Jain, et al; Blood 2019; 134 (Supplement_1): 2885. doi: https://doi.org/10.1182/blood-2019-131041 Figure 1 Figure 1. Disclosures Eckard: Amphivena Therapeutics: Current Employment. Rojo: Amphivena Therapeutics: Current Employment. Smith: Amphivena Therapeutics: Current Employment. Chun: Amphivena Therapeutics: Current Employment.

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