Lenalidomide-based response-adapted therapy for older adults without high risk myeloma.

Combined lenalidomide and dexamethasone is a standard-of-care therapy for the treatment of older adults with multiple myeloma. Lenalidomide monotherapy has not been evaluated in newly diagnosed myeloma patients. We conducted a phase II study, evaluating a response-adapted therapy for older adults newly diagnosed with multiple myeloma without high-risk features who were ineligible for high-dose therapy and stem cell transplant. Patients were started on single-agent lenalidomide, and low-dose dexamethasone was added in the event of progressive disease, in a response-adapted approach. The primary endpoint was progression-free survival (PFS), and the International Myeloma Working Group's uniform response criteria were used to assess response and progression. Twenty-seven patients were enrolled, and 20 (74%) experienced a partial response or better to this response-adapted therapy. After a median follow-up of 69 months, the median PFS was 36 months [95% confidence interval (CI), 29·8 to not reached], and the median overall survival was 65 months (95% CI, 35·3 to not reached). Grade 3/4 adverse events were mainly haematological in nature. This response-adapted therapy in this patient population is feasible and results in durable responses that compare favourably with concurrent lenalidomide and dexamethasone. These results should be validated in prospective studies.

WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides.

Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials.

Developing strategies in the immunotherapy of leukemias.

BACKGROUND: In the current treatment paradigms for leukemias, hematopoietic stem cell transplant (HSCT) is considered the best option with a curative potential although more often than not it simply delays disease progression. Advances are needed, both in current therapies and in the development of new strategies. Partly from studying the nuances of the curative potential of stem cell transplant, we have come to appreciate the relevance of the immune response and the potential of immunotherapy. METHODS: This review article summarizes the recent advances in the field of immunology and immunotherapy for leukemia. RESULTS: In passive immunotherapy, recent progress in chimeric T-cell antigen receptor technology has been encouraging. In active immunotherapy, a cancer vaccine may potentially enhance HSCT. An overview of various clinical studies of peptide vaccination strategies focusing on molecular targets such as the Wilms' tumor gene 1 (WT1), proteinase 3 (PR3), and receptor for hyaluronan acid-mediated motility (RHAMM) is provided. Cell-based vaccination strategies are also briefly explored. CONCLUSIONS: The immune system clearly has the capacity to recognize and react to leukemic cells, and recent evidence directs our attention to the importance of mounting inflammatory and CD4 T-cell responses to complement and support the cytotoxic activity elicited by peptide vaccines.

Survivin Dendritic Cell Vaccine Safely Induces Immune Responses and Is Associated with Durable Disease Control after Autologous Transplant in Patients with Myeloma.

PURPOSE: We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma. PATIENTS AND METHODS: This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified. RESULTS: A total of 14 patients were treated and 13 included in the primary efficacy analysis. No serious adverse events were attributed to DC:Ad-S vaccine. Detectable anti-survivin antibodies increased from baseline in 9 of 13 (69%) patients, and 11 of 13 (85%) mounted either a cellular or humoral immune response to survivin. Seven patients had an improved clinical response at day +90, all of whom had mounted an immune response, and 6 of 7 patients remain event-free at a median follow-up of 4.2 years. Estimated progression-free survival at 4 years is 71% (95% confidence interval, 41-88). CONCLUSIONS: Two doses of DC:Ad-S, one given immediately before and another after ASCT, were feasible and safe. A high frequency of vaccine-specific immune responses was seen in combination with durable clinical outcomes, supporting ongoing investigation into the potential of this approach. See related commentary by Dhodapkar, p. 4524.

CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial.

BACKGROUND: CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01. The aim of the present study was to determine the safety and recommended phase 2 dosing of CYAD-01 administered without preconditioning or bridging chemotherapy. METHODS: The multicentre THINK study was an open-label, dose-escalation, phase 1 study for patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, or multiple myeloma, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium. The dose-escalation segment evaluated three dose levels: 3 × 108 (dose level one), 1 × 109 (dose level two), and 3 × 109 (dose level three) cells per infusion with a 3 + 3 Fibonacci study design using a schedule of three infusions at 2-week intervals followed by potential consolidation treatment consisting of three additional infusions. The occurrence of dose-limiting toxicities post-CYAD-01 infusion was assessed as the primary endpoint in the total treated patient population. The trial was registered with ClinicalTrials.gov, NCT03018405, and EudraCT, 2016-003312-12, and has been completed. FINDINGS: Between Feb 6, 2017, and Oct 9, 2018, 25 patients were registered in the haematological dose-escalation segment. Seven patients had manufacturing failure for insufficient yield and two had screening failure. 16 patients were treated with CYAD-01 (three with multiple myeloma and three with acute myeloid leukaemia at dose level one; three with acute myeloid leukaemia at dose level two; and six with acute myeloid leukaemia and one with myelodysplastic syndromes at dose level three). Median follow-up was 118 days (IQR 46-180). Seven patients (44%) had grade 3 or 4 treatment-related adverse events. In total, five patients (31%) had grade 3 or 4 cytokine release syndrome across all dose levels. One dose-limiting toxicity of cytokine release syndrome was reported at dose level three. No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Three (25%) of 12 evaluable patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndromes had an objective response. Among responders, two patients with acute myeloid leukaemia proceeded to allogeneic haematopoietic stem-cell transplantation (HSCT) after CYAD-01 treatment, with durable ongoing remissions (5 and 61 months). INTERPRETATION: Treatment with a multiple CYAD-01 infusion schedule without preconditioning is well tolerated and shows anti-leukaemic activity, although without durability outside of patients bridged to allogeneic HSCT. These phase 1 data support the proof-of-concept of targeting NKG2D ligands by CAR T-cell therapy. Further clinical studies with NKG2D-based CAR T-cells are warranted, potentially via combinatorial antigen targeted approaches, to improve anti-tumour activity. FUNDING: Celyad Oncology.

Cardiac events after standard of care idecabtagene vicleucel for relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited.

Adding Cyclophosphamide to Bortezomib and Dexamethasone was not Associated With Improved Outcomes of Patients With Newly Diagnosed Light Chain Amyloidosis: A Retrospective Study.

INTRODUCTION: Before 2021, the combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was one of the most used upfront therapy for systemic immunoglobulin light chain (AL) amyloidosis. Recently, daratumumab in combination with VCd resulted in improved outcomes compared to VCd. However, it's still unclear the role of cyclophosphamide in this combination. MATERIALS AND METHODS: We conducted this retrospective single-institutional study to compare the outcomes of upfront bortezomib and dexamethasone with or without cyclophosphamide (VD vs. VCd). RESULTS: Of 136 total patients, 62 received VD and 74 received VCd. The median age was 64 and the median number of organs involved was 2. Hematologic response was achieved among 73.4% patients in the VD arm and 85.9% in the VCd arm at 3 months (P = .15). Best organ response was not different between 2 arms (34.1% vs. 52.9% for VD and VCd arms, respectively; P = .28). After a median follow-up of 24.4 months, 2-year OS for VD and VCd arm was 70.6% and 84.6% respectively. The median overall survival was 70 months for VD arm and not reached for VCd arm (P = .30). There was no statistically significant difference in median time to next therapy (9.3 vs. 13.5 months for VD and VCd arms, respectively. P = .99). CONCLUSION: the addition of cyclophosphamide to VD was not associated with improved outcomes of patients with AL amyloidosis in this retrospective study.

Racial and ethnic differences in clonal hematopoiesis, tumor markers, and outcomes of patients with multiple myeloma.

Multiple myeloma (MM) incidence, mortality, and survival vary by race and ethnicity, but the causes of differences remain unclear. We investigated demographic, clinical, and molecular features of diverse MM patients to elucidate mechanisms driving clinical disparities. This study included 495 MM patients (self-reported Hispanic, n = 45; non-Hispanic Black, n = 52; non-Hispanic White, n = 398). Hispanic and non-Hispanic Black individuals had an earlier age of onset than non-Hispanic White individuals (53 and 57 vs 63 years, respectively, P < .001). There were no differences in treatment by race and ethnicity groups, but non-Hispanic Black patients had a longer time to hematopoietic cell transplant than non-Hispanic White patients (376 days vs 248 days; P = .01). Overall survival (OS) was improved for non-Hispanic Black compared with non-Hispanic White patients (HR, 0.50; 95% CI, 0.31-0.81; P = .005), although this association was attenuated after adjusting for clinical features (HR, 0.62; 95% CI, 0.37-1.03; P = .06). Tumor mutations in IRF4 were most common in Hispanic patients, and mutations in SP140, AUTS2, and SETD2 were most common in non-Hispanic Black patients. Differences in tumor expression of BCL7A, SPEF2, and ANKRD26 by race and ethnicity were observed. Clonal hematopoiesis was detected in 12% of patients and associated with inferior OS in non-Hispanic Black patients compared with patients without clonal hematopoiesis (HR, 4.36; 95% CI, 1.36-14.00). This study provides insight into differences in molecular features that may drive clinical disparities in MM patients receiving comparable treatment, with the novel inclusion of Hispanic individuals.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

High-Dimensional Flow Cytometry Analysis of Regulatory Receptors on Human T Cells, NK Cells, and NKT Cells.

The field of flow cytometry has witnessed rapid technological advancements in the last few decades. While the founding principles of fluorescent detection on cells (or particles) within a uniform fluid stream remains largely unchanged, the availability more sensitive cytometers with the ability to multiplex more and more florescent signals has resulted in very complex high-order assays. This results in the co-use of fluorophores with increased levels of emission overlap and/or spillover spreading than in years past and thus requires careful and well thought out planning for flow cytometry assay development. As an example, we present the development of a large 18-color (20 parameter) flow cytometry assay designed to take an in depth analysis of effector lymphocyte phenotypes, with careful attention to assay controls and panel design.

Plasma cell dependence on histone/protein deacetylase 11 reveals a therapeutic target in multiple myeloma.

The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity may increase the clinical effectiveness of HDAC inhibitors. We demonstrated that plasma cell development and survival are dependent upon HDAC11, suggesting this enzyme is a promising therapeutic target in MM. Mice lacking HDAC11 exhibited markedly decreased plasma cell numbers. Accordingly, in vitro plasma cell differentiation was arrested in B cells lacking functional HDAC11. Mechanistically, we showed that HDAC11 is involved in the deacetylation of IRF4 at lysine103. Further, targeting HDAC11 led to IRF4 hyperacetylation, resulting in impaired IRF4 nuclear localization and target promoter binding. Importantly, transient HDAC11 knockdown or treatment with elevenostat, an HDAC11-selective inhibitor, induced cell death in MM cell lines. Elevenostat produced similar anti-MM activity in vivo, improving survival among mice inoculated with 5TGM1 MM cells. Elevenostat demonstrated nanomolar ex vivo activity in 34 MM patient specimens and synergistic activity when combined with bortezomib. Collectively, our data indicated that HDAC11 regulates an essential pathway in plasma cell biology establishing its potential as an emerging theraputic vulnerability in MM.

The potential of ixazomib, a second-generation proteasome inhibitor, in the treatment of multiple myeloma.

The therapeutic armamentarium for multiple myeloma has recently benefited from the addition of several new agents (including second-generation proteasome inhibitors, monoclonal antibodies and histone deacetylase inhibitors). This review will focus on ixazomib, an orally bioavailable second-generation proteasome inhibitor. Specifically, we will review the preclinical data, clinical trial experience, potential indications as well as unanswered questions pertaining to this new agent in multiple myeloma.

Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types.

INTRODUCTION: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. METHODS AND ANALYSIS: This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×108, 1×109 and 3×109 NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT03018405, EudraCT 2016-003312-12; Pre-result.

Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens.

A better understanding of how solid malignancies arise in an immunocompetent host, avoid immune recognition, and ultimately progress to widely disseminated cancer is essential to effectively harness the immune system against solid tumors. Because of their extra-lymphatic localization, it has been proposed that solid malignancies are just ignored by the immune system, thereby allowing their uncontrolled growth and dissemination. Alternatively, as most of the solid tumors are unable to express costimulatory molecules, the "signal one without signal two" model of tolerance induction has been frequently evoked to account for the failure of the immune system to reject antigenic tumors in vivo. In this study, we showed, however, that the extra-lymphatic growth of solid tumors is not immunologically ignored by the lymphoid compartment, resulting instead in the early induction of antigen-specific CD4(+) T-cell tolerance. Furthermore, analysis of parent-into-F1 bone marrow (BM) chimeras demonstrates that presentation of tumor antigens by BM-derived antigen-presenting cells represents the dominant mechanism in solid tumor-induced CD4(+) T-cell tolerance. Our findings of early development of antigen-specific T-cell unresponsiveness mediated by BM-derived antigen-presenting cells, not only provides a plausible explanation for the failure of the immune system to reject antigenic solid tumors in vivo, but more importantly, they have identified a barrier that, if appropriately manipulated, may lead to approaches to effectively harness the immune system against solid malignancies.

Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.

T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3zeta chain and impairs T-cell responses. Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in the tumor microenvironment and could decrease CD3zeta expression and impair T-cell function. The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. Arginase I expression in the tumor was seen on day 7 after tumor injection. Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate L-Arginine (L-Arg) and deplete extracellular L-Arg in vitro. L-Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3zeta in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. The injection of the arginase inhibitor N-hydroxy-nor-L-Arg blocked growth of s.c. 3LL lung carcinoma in mice. High levels of arginase I were also found in tumor samples of patients with non-small cell carcinoma. Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.

Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab (anti-PD-1) treatment.

Aldesleukin [interleukin-2 (IL-2)] induces durable complete responses in some kidney cancer and melanoma patients. Nivolumab is an investigational antibody drug targeting programmed death-1 (PD-1) as a treatment, demonstrating activity in multiple cancer types. An expanding complement of immunotherapeutics raises important issues regarding the best way to use them. There are issues beyond identifying an agent that provides the superior front-line response: when does one therapy potentiate another immune therapy? When is the capacity of immune response exhausted and an approach without immune mechanism the better therapy? In this case report, we present a patient with metastatic renal cell carcinoma with no tumor regression evident on a PD-1 blockade (given on an investigational trial), who then achieved near-complete response to bolus high-dose IL-2 therapy, maintaining a persistent response off therapy. This case emphasizes on the need to develop improved predictors of response to immune therapies, especially as they can be applied to optimize sequential immunotherapeutic modalities versus predict when to turn to alternative targeted agents in renal cell carcinoma, and is an example of efficacious IL-2 application as a second-line treatment.

Enhanced CD8 T cell cross-presentation by macrophages with targeted disruption of STAT3.

CD8 T cell tolerance, once thought to be largely a result of clonal deletion, is now appreciated to be much more complex, additionally involving multiple permutations of partial loss of effector function in residual clonal populations. This is especially important in the context of tumor immunity, in which persistent tolerized cytotoxic CD8 T cells (CTL), if reactivated, could potentially mount a protective response. Previously we have shown that antigen-presenting cells (APCs) with a targeted disruption of STAT3 break tolerance in CD4 T cells. Here we evaluate the STAT3-defective APC in terms of its ability to induce a productive CTL response. Our data demonstrate that macrophages derived from conditional STAT3 knockout mice are superior to wild-type macrophages in terms of their ability to prime cognate CTL responses, and to cross-present tumor-derived antigen to CTLs in vitro. CTLs cultured with STAT3-deficient APCs demonstrated a stronger proliferative response and produced increased amounts of IFN-gamma and TNF-alpha, all of which have been shown to be diminished in tumor-tolerized CD8 T cells. Targeting STAT3 signaling represents therefore an enticing strategy to augment CTL responses in the tumor-bearing host.