Bispecific targeting of CD20 and CD19 increases polyfunctionality of chimeric antigen receptor T-cell products in B-cell malignancies.

BACKGROUND AIMS: Selective immune pressure contributes to relapse due to target antigen downregulation in patients treated with anti-CD19 chimeric antigen receptor (CAR) T cells. Bispecific lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells may prevent progression/relapse due to antigen escape. Highly polyfunctional T cells within a CAR T-cell product have been associated with response in single-antigen-targeted anti-CD19 CAR T cells. METHODS: The authors performed a single-cell proteomic analysis to assess polyfunctional cells in our LV20.19 CAR T-cell product. Analysis was limited to those treated at a fixed dose of 2.5 × 106 cells/kg (n = 16). Unused pre-infusion CAR T cells were thawed, sorted into CD4/CD8 subsets and stimulated with K562 cells transduced to express CD19 or CD20. Single-cell production of 32 individual analytes was measured and polyfunctionality and polyfunctional strength index (PSI) were calculated. RESULTS: Fifteen patients had adequate leftover cells for analysis upon stimulation with CD19, and nine patients had adequate leftover cells for analysis upon stimulation with CD20. For LV20.19 CAR T cells, PSI was 866-1109 and polyfunctionality was 40-45%, which were higher than previously reported values for other CAR T-cell products. CONCLUSIONS: Stimulation with either CD19 or CD20 antigens resulted in similar levels of analyte activation, suggesting that this product may have efficacy in CD19- patient populations.

Long-term outcomes and predictors of early response, late relapse, and survival for patients treated with bispecific LV20.19 CAR T-cells.

We previously reported results of a first-in-human trial of bispecific LV20.19 chimeric antigen receptor T-cell (CAR-T) therapy, demonstrating high response rates in patients with relapsed, refractory (R/R) B-cell malignancies. We now report two-year survival outcomes and predictors of early response, late relapse, and survival. Patients from the previously reported phase 1 dose escalation and expansion trial of LV20.19 CAR-T therapy (NCT03019055) treated at target dose of 2.5 × 106 cells/kg (n = 16) were included in this updated analysis. Two-year progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. The relationship of in-vivo CAR-T expansion, tumor burden, and effector: target ratio on early response (day 28) and late relapse (>180 days post-CAR-T) were assessed. Exact log-rank testing was performed to evaluate the impacts of clinical variables on survival outcomes. With a median of 31 months (range 27-40) of follow-up, two-year PFS and OS were 44% and 69%. Median PFS and OS were 15.6 months and not reached, respectively. For CAR-naïve large B-cell lymphoma patients (n = 8), two-year PFS and OS were 50% and 75%. No patient with progression experienced dual target antigen (CD19 or CD20) loss on post-relapse biopsy. Lower in vivo expansion was strongly associated with late relapse. Early treatment response was impeded by high metabolic tumor volume and low effector: target ratio. Bridging therapy and higher absolute lymphocyte count on day of CAR-T infusion were associated with inferior survival outcomes. In conclusion, this initial trial of LV20.19 CAR-T demonstrates a signal for favorable long-term outcomes for patients with R/R B-cell malignancies.

Manufacturing chimeric antigen receptor T cells from cryopreserved peripheral blood cells: time for a collect-and-freeze model?

BACKGROUND AIMS: Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized outcomes for patients with relapsed/refractory B-cell malignancies. Despite the exciting results, several clinical and logistical challenges limit its wide applicability. First, the apheresis requirement restricts accessibility to institutions with the resources to collect and process peripheral blood mononuclear cells (PBMCs). Second, even when utilizing an apheresis product, failure to manufacture CAR T cells is a well-established problem in a significant subset. In heavily pre-treated patients, prior chemotherapy may impact T-cell quality and function, limiting the ability to manufacture a potent CAR T-cell product. Isolation and storage of T cells shortly after initial cancer diagnosis or earlier in life while an individual is still healthy are an alternative to using T cells from heavily pre-treated patients. The goal of this study was to determine if a CAR T-cell product could be manufactured from a small volume (50 mL) of healthy donor blood. METHODS: Collaborators at Cell Vault collected 50 mL of whole peripheral venous blood from three healthy donors. PBMCs were isolated, cryopreserved and shipped to the Medical College of Wisconsin. PBMCs for each individual donor were thawed, and CAR T cells were manufactured using an 8-day process on the CliniMACS Prodigy device with a CD19 lentiviral vector. RESULTS: Starting doses of enriched T-cell numbers ranged from 4.0 × 107 cells to 4.8 × 107 cells, with a CD4/CD8 purity of 74-79% and an average CD4:CD8 ratio of 1.4. On the day of harvest, total CD3 cells in the culture expanded to 3.6-4.6 × 109 cells, resulting in a 74- to 115-fold expansion, an average CD4:CD8 ratio of 2.9 and a CD3 frequency of greater than 99%. Resulting CD19 CAR expression varied from 19.2% to 48.1%, with corresponding final CD19+ CAR T-cell counts ranging from 7.82 × 108 cells to 2.21 × 109 cells. The final CAR T-cell products were phenotypically activated and non-exhausted and contained a differentiated population consisting of stem cell-like memory T cells. CONCLUSIONS: Overall, these data demonstrate the ability to successfully generate CAR T-cell products in just 8 days using cryopreserved healthy donor PBMCs isolated from only 50 mL of blood. Notably, numbers of CAR T cells were more than adequate for infusion of an 80-kg patient at dose levels used for products currently approved by the Food and Drug Administration. The authors offer proof of principle that cryopreservation of limited volumes of venous blood with an adequate starting T-cell count allows later successful manufacture of CAR T-cell therapy.

Utilization and Cost Implications of Hematopoietic Progenitor Cells Stored for a Future Salvage Autologous Transplantation or Stem Cell Boost in Myeloma Patients.

Autologous hematopoietic cell transplantation (autoHCT) is a standard initial treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient hematopoietic progenitor cells (HPCs) for 2 autoHCTs in all eligible patients. Despite a lack of published data on the utilization of HPCs stored for future use, it is common practice across transplantation programs to collect enough HPCs for 2 autoHCTs in MM patients. In this single-center retrospective study, we analyzed the utilization of HPCs collected and stored at the time of first autoHCT in patients with MM, along with the cost implications of HPC collection targets sufficient for 2 transplantations. In a cohort of 400 patients (median age, 63 years; range, 22 to 79 years), after a median follow-up of 50.4 months, 197 patients had relapsed and 36 had received HPC infusion as salvage autoHCT (n = 29) and/or HPC boost (n = 8). In this cohort, a median CD34+ cell dose of 4.3 × 106/kg (range, 1.1 to 12.94.3 × 106/kg) was used for first autoHCT, and a median of 4.4 × 106/kg (range, 1.0 to 20.2× 106/kg) CD34+ cells were stored for future use. At 6 years after the first autoHCT, the estimated cumulative incidence of salvage autoHCT was 12.0% without HPC boost and 13.9% with HPC boost. HPC utilization was significantly higher in the 60- to 64-year age group, whereas no patients who were age ≥70 years at the time of first autoHCT received salvage autoHCT. Using the CD34+ cell dose infused during the first autoHCT as the cutoff for individual patients, the estimated mean additional cost of HPC collection intended for subsequent use (over and above the HPCs used for first autoHCT) was $10,795 ($4.32 million for the entire cohort), an estimated 14% of which (ie, $583,600) was actually used up in salvage autoHCT by 6 years from first autoHCT. In conclusion, our results suggest the need for reappraisal of HPC collection targets for salvage autoHCT and argue against HPC collection and storage for salvage autoHCT in patients age ≥70 years at the time of first autoHCT.

Bone Marrow-derived CD8+ T Cells From Pediatric Leukemia Patients Express PD1 and Expand Ex Vivo Following Induction Chemotherapy.

Adoptive cell therapy (ACT) of chimeric antigen receptor T cells has demonstrated remarkable success for the treatment of pediatric B-cell leukemia. For patients who are not candidates for chimeric antigen receptor T-cell therapy, ACT using tumor antigen-experienced polyclonal T cells may be a treatment option. Since leukemic blasts reside in the bone marrow and bone marrow is a preferred site for homeostatic proliferation of cytotoxic memory CD8 T cells, we hypothesized that bone marrow would be a source of activated T cells. The aim of this study was to determine the feasibility of using bone marrow-derived T cells following postinduction chemotherapy for use in adoptive cell transfer. Matched patient samples of bone marrow and peripheral blood-derived T cells expanded ex vivo and displayed similar apoptotic profiles. Before activation and expansion, there was a significant increase in the percentage of bone marrow-derived CD8 T cells expressing activation markers PD1, CD45RO, and CD69 as compared with peripheral blood CD8 T cells. Considering, melanoma-reactive CD8 T cells reside in the subset of PD1CD8 T cells, the bone marrow may be an enriched source leukemic-specific T cells that can be used for ACT.

An updated single center experience with plerixafor and granulocyte colony-stimulating factor for stem cell mobilization in light chain amyloidosis.

The use of granulocyte-colony stimulating factor (G-CSF) with or without chemotherapy to mobilize hematopoietic progenitor cells (HPCs) can result in significant morbidity in light chain (AL) amyloidosis patients. Plerixafor, a strong inducer and mobilizer of HPCs, can be used as an adjunct to G-CSF to improve mobilization efficiency. We describe the outcomes for combined G-CSF/plerixafor mobilized patients with AL amyloidosis. We reviewed data of 53 consecutive AL amyloidosis patients who underwent combined G-CSF/plerixafor HPC mobilization between May 2011 and October 2017 at our institution. We evaluated patients for HPC collection efficiency, perimobilization toxicity and postautologous hematopoietic cell transplantation (autoHCT) outcomes. Median CD34+ cell collection was 12.4 × 106 cells/kg (range 2.5 × 106 to 34.1 × 106 cells/kg) and 45 (85%) patients had collections of ≥5.0 × 106 CD34+ cells/kg. There were no mobilization failures or perimobilization mortality. During mobilization, 37 (70%) patients had weight gain (median 1.3 kg, range 0.1-4) but none >10% body weight, 5 (10%) patients had diarrhea, and one patient each had hypotension and cardiac arrhythmia. Among the 31 patients analyzed for CD34 collection efficiency (CE), the median CD34 CE was 47% (range 36-62). At 5 years follow-up 82% and 84% of patients were progression-free and alive, respectively. Our results suggest that G-CSF/plerixafor mobilization is safe, well tolerated, and effective in AL amyloidosis.

Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma.

Early phase clinical trials targeting the programmed death receptor-1/ligand-1 (PD-1/PD-L1) pathway to overcome tumor-mediated immunosuppression have reported promising results for a variety of cancers. This pathway appears to play an important role in the failure of immune reactivity to malignant plasma cells in multiple myeloma patients, as the tumor cells express relatively high levels of PD-L1, and T cells show increased PD-1 expression. In the current study, we demonstrate that PD-1/PD-L1 blockade with a PD-L1-specific Ab elicits rejection of a murine myeloma when combined with lymphodepleting irradiation. This particular combined approach by itself has not previously been shown to be efficacious in other tumor models. The antitumor effect of lymphodepletion/anti-PD-L1 therapy was most robust when tumor Ag-experienced T cells were present either through cell transfer or survival after nonmyeloablative irradiation. In vivo depletion of CD4 or CD8 T cells completely eliminated antitumor efficacy of the lymphodepletion/anti-PD-L1 therapy, indicating that both T cell subsets are necessary for tumor rejection. Elimination of myeloma by T cells occurs relatively quickly as tumor cells in the bone marrow were nearly nondetectable by 5 d after the first anti-PD-L1 treatment, suggesting that antimyeloma reactivity is primarily mediated by preactivated T cells, rather than newly generated myeloma-reactive T cells. Anti-PD-L1 plus lymphodepletion failed to improve survival in two solid tumor models, but demonstrated significant efficacy in two hematologic malignancy models. In summary, our results support the clinical testing of lymphodepletion and PD-1/PD-L1 blockade as a novel approach for improving the survival of patients with multiple myeloma.

Exciting new murine model of cGVHD.

In this issue of Blood, Srinivasan et al report that mice conditioned for allogeneic hematopoietic stem cell transplantation with cyclophosphamide and total body irradiation develop wide-spectrum manifestations of chronic graft-versus-host disease (cGVHD).1 This represents an exciting new preclinical model that can be used to uncover mechanisms of cGVHD and test interventional therapies.

Depletion of CD25⁺ T cells from hematopoietic stem cell grafts increases posttransplantation vaccine-induced immunity to neuroblastoma.

A multifaceted immunotherapeutic strategy that includes hematopoietic stem cell (HSC) transplantation, T-cell adoptive transfer, and tumor vaccination can effectively eliminate established neuroblastoma tumors in mice. In vivo depletion of CD4⁺ T cells in HSC transplantation recipients results in increased antitumor immunity when adoptively transferred T cells are presensitized, but development of T-cell memory is severely compromised. Because increased percentages of regulatory T (Treg) cells are seen in HSC transplantation recipients, here we hypothesized that the inhibitory effect of CD4⁺ T cells is primarily because of the presence of expanded Treg cells. Remarkably, adoptive transfer of presensitized CD25-depleted T cells increased tumor vaccine efficacy. The enhanced antitumor effect achieved by ex vivo depletion of CD25⁺ Treg cells was similar to that achieved by in vivo depletion of all CD4⁺ T cells. Depletion of CD25⁺ Treg cells resulted in elevated frequencies of tumor-reactive CD8 and CD4⁺ T cells and increased CD8-to-Treg cell ratios inside tumor masses. All mice given presensitized CD25-depleted T cells survived a tumor rechallenge, indicating the development of long-term CD8⁺ T-cell memory to tumor antigens. These observations should aid in the future design of immunotherapeutic approaches that promote the generation of both acute and long-term antitumor immunity.

Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone.

Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria-targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria-targeted atovaquone treatment led to significant reductions of both granulocytic myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria-targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic-myeloid-derived suppressor cells and regulatory T cells, which may lead to death of granulocytic-myeloid-derived suppressor cells and regulatory T cells. Mitochondria-targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic-myeloid-derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic-myeloid-derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor-infiltrating CD4+ T cells. Mitochondria-targeted atovaquone also improves the anti-tumor activity of PD-1 blockade immunotherapy. The results implicate granulocytic-myeloid-derived suppressor cells and regulatory T cells as novel targets of mitochondria-targeted atovaquone that facilitate its antitumor efficacy.

The effect of tocilizumab on patient reported outcomes and inflammatory biomarkers in hematopoietic cell transplantation.

Inflammatory physiology has been linked to behavioral and emotional symptoms in a variety of contexts and experimental paradigms. Hematopoietic cell transplantation (HCT) represents an intersection of significant immune dysregulation and psychosocial stress, and this biobehavioral relationship can influence important clinical outcomes. For those undergoing HCT with inflammation-related neuropsychiatric symptoms, using targeted agents such as the IL-6 receptor antagonist tocilizumab may be an effective therapeutic approach. We conducted an observational cohort study to explore patient reported outcomes (PROs) and inflammatory biomarkers among allogeneic HCT recipients who received tocilizumab compared to those who did not. Individuals on a larger trial of tocilizumab for prevention of graft-versus-host disease received a single dose of tocilizumab 24 h prior to stem cell infusion. Measures of anxiety, depression, pain, fatigue, and sleep quality and parallel blood samples for inflammatory cytokines were collected from participants and an analogous comparison cohort at baseline and Day 28 after stem cell infusion. Demographic and medical characteristics were reported; an analysis of covariance regression model was fitted to evaluate differences in PROs and distance correlation t-tests assessed for associations between biomarkers and PRO measures. For n = 18 tocilizumab-treated and n = 22 comparison patients, there were no significant differences between patient demographics, but the tocilizumab cohort had a different distribution of primary diagnoses (p = 0.009) with more patients with leukemias and a higher proportion of patients in their first remission (64% vs 28%, p = 0.024). Depression was higher at Day 28 compared to baseline in both groups (comparison group: +5.1 [95% CI 0.14-10, p = 0.045], tocilizumab: +8.6 [95% CI 2.3-15, p = 0.011]), though the difference between groups did not reach statistical significance. The tocilizumab group had significantly increased circulating IL-6 and decreased CRP at Day 28 (all p < 0.05). There was an association between collective baseline biomarkers and PROs (distance correlation dCor = 0.110, p = 0.005), but this same association was not present at Day 28 (dCor = -0.001, p = 0.5). In univariate analyses, a 10-fold increase in plasma IL-6 was associated with a 3.6-point higher depression score (95% CI 1.0-6.2, p = 0.008). In this exploratory analysis of PROs and inflammatory biomarkers in patients undergoing HCT, tocilizumab was not associated with favorable patient-reported symptom profiles. This finding is aligned with our prior work in the HCT population but diverges from hypothesized therapeutic effects of tocilizumab on depressive symptoms, thus highlighting the need for larger prospective translational studies in biobehavioral HCT research.

Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade.

Multiple myeloma is an incurable plasma cell malignancy. Patients who fail conventional therapy are frequently treated with hematopoietic stem cell transplantation (HSCT), which results in reduced tumor burden, but the patients subsequently relapse from sites of chemotherapy-resistant disease. Using the 5T33 murine model of myeloma and a previously successful immunotherapy regimen consisting of autologous (syngeneic) HSCT and cell-based vaccine administration, we were unable to improve survival of myeloma-bearing mice. The 5T33 tumor line, similar to malignant plasma cells from myeloma patients, expresses high levels of programmed death receptor ligand-1 (PD-L1), which binds to the inhibitory receptor, PD-1. We observed that T cells from myeloma-bearing mice express high levels of PD-1, which has also been observed in patients with multiple myeloma. These PD-1(+) T cells were exhausted and produced IL-10. Based on these observations, we combined HSCT with whole-cell vaccination and PD-L1 blockade. Inhibition of the PD-1/PD-L1 pathway with HSCT and whole-cell vaccination increased the survival of myeloma-bearing mice from 0% to 40%. These data demonstrate a role for PD-L1 in suppressing immune responses to myeloma and suggest that blockade of this pathway may enhance immunotherapy for this disease.

Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of antitumor immune memory.

High-risk neuroblastoma remains a clinically challenging disease. Here, we report that a multifaceted immunotherapeutic approach including syngeneic hematopoietic stem cell transplantation (HSCT), adoptive transfer of sensitized T cells (from syngeneic donors vaccinated to tumor antigens), and early posttransplantation tumor vaccination can effectively treat mice with established neuroblastoma. Vaccination was an important component of this immunotherapy, as it resulted in enhanced and prolonged tumor-specific CD8 T-cell activity and improved antitumor efficacy. Surprisingly, CD4 cell depletion of mice given sensitized T cells resulted in better tumor-free survival, which was associated with an early increased expansion of CD8 T cells with an effector phenotype, increased numbers of tumor-reactive CD8 T cells, and increased tumor infiltration by CD8 T cells. However, in the absence of CD4 T cells, development of long-term tumor immunity (memory) was severely compromised as reflected by diminished CD8 T-cell recall responses and an inability to resist tumor rechallenge in vivo. Based on these results, a major challenge with this immunotherapeutic approach is how to obtain the ideal initial antitumor response but still preserve antitumor immune memory. These data suggest that identification and selective depletion of immune inhibitory CD4 T cells may be a strategy to enhance early antitumor immunity and induce a long-lasting tumor response after HSCT.

Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression.

Metabolic heterogeneity within the tumor microenvironment promotes cancer cell growth and immune suppression. We determined the impact of mitochondria-targeted complex I inhibitors (Mito-CI) in melanoma. Mito-CI decreased mitochondria complex I oxygen consumption, Akt-FOXO signaling, blocked cell cycle progression, melanoma cell proliferation and tumor progression in an immune competent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within and halted tumor cell proliferation, it also elevated infiltration of activated effector T cells and decreased myeloid-derived suppressor cells (MDSC) as well as tumor-associated macrophages (TAM) in melanoma tumors in vivo. Anti-proliferative doses of Mito-CI inhibited differentiation, viability, and the suppressive function of bone marrow-derived MDSC and increased proliferation-independent activation of T cells. These data indicate that targeted inhibition of complex I has synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling.

STING Activated Tumor-Intrinsic Type I Interferon Signaling Promotes CXCR3 Dependent Antitumor Immunity in Pancreatic Cancer.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a lethal chemoresistant cancer that exhibits early metastatic spread. The highly immunosuppressive PDA tumor microenvironment renders patients resistant to emerging immune-targeted therapies. Building from our prior work, we evaluated stimulator of interferon genes (STING) agonist activation of PDA cell interferon-α/ß-receptor (IFNAR) signaling in systemic antitumor immune responses. METHODS: PDA cells were implanted subcutaneously to wild-type, IFNAR-, or CXCR3-knockout mice. Tumor growth was monitored, and immune responses were comprehensively profiled. RESULTS: Human and mouse STING agonist ADU-S100 reduced local and distal tumor burden and activated systemic antitumor immune responses in PDA-bearing mice. Effector T-cell infiltration and inflammatory cytokine and chemokine production, including IFN-dependent CXCR3-agonist chemokines, were elevated, whereas suppressive immune populations were decreased in treated tumors. Intratumoral STING agonist treatment also generated inflammation in distal noninjected tumors and peripheral immune tissues. STING agonist treatment of type I IFN-responsive PDA tumors engrafted to IFNAR-/- recipient mice was sufficient to contract tumors and stimulate local and systemic T-cell activation. Tumor regression and CD8+ T-cell infiltration were abolished in PDA engrafted to CXCR3-/- mice treated with STING agonist. CONCLUSIONS: These data indicate that STING agonists promote T-cell infiltration and counteract immune suppression in locally treated and distant tumors. Tumor-intrinsic type I IFN signaling initiated systemic STING-mediated antitumor inflammation and required CXCR3 expression. STING-mediated induction of systemic immune responses provides an approach to harness the immune system to treat primary and disseminated pancreatic cancers.

Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA.

Expressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8+ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine.

Translational Advances in Cancer Prevention Agent Development (TACPAD) Virtual Workshop on Immunomodulatory Agents: Report.

The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) convened the "Translational Advances in Cancer Prevention Agent Development (TACPAD) Workshop on Immunomodulatory Agents" as a virtual 2-day workshop on September 13 to 14, 2021. The main goals of this workshop were to foster the exchange of ideas and potentially new collaborative interactions among leading cancer immunoprevention researchers from basic and clinical research and highlight new and emerging trends in immunoprevention. The workshop included an overview of the mechanistic classes of immunomodulatory agents and three sessions covering the gamut from preclinical to clinical studies. The workshop convened individuals working in immunology and cancer prevention to discuss trends in discovery and development of immunomodulatory agents individually and in combination with other chemopreventive agents or vaccines.

Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting.

The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented.

Tumor antigen analysis in neuroblastoma by serological interrogation of bioinformatic data.

The identification of tumor antigens remains a major objective in tumor immunology, especially in pediatric malignancies where solid tumors often do not express a single dominant antigen. Methods such as the Serological Screening of Recombinant cDNA Expression Libraries (SEREX) have been used in the discovery of tumor-expressed proteins by virtue of their ability to induce an antibody response. To focus and accelerate this approach, we first identified candidate antigens by gene expression profiling data from clinical neuroblastoma specimens and then used an animal model to generate an antibody response to an engineered cell-based vaccine. Candidate tumor antigens were expressed as recombinant proteins in a mammalian system and screened for antibody recognition using serum from mice vaccinated with a neuroblastoma cell-based vaccine engineered to express CD80 and CD86, with or without Treg depletion. Through this procedure, the never in mitosis A (NIMA)-related kinase NEK2 was identified as a tumor-associated antigen. Direct testing of serum from patients newly diagnosed with neuroblastoma showed specific serological responses in two of 20 patients. Although NEK2 was not universally recognized, it may serve as a tumor antigen for some patients.