Meenal Sinha

University of California, San Francisco

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Lawrence Fong

UCSF Helen Diller Family Comprehensive Cancer Center

Alexander Cheung

University of California, San Francisco

Li Zhang

University of California, San Francisco

Terence W. Friedlander

UCSF Helen Diller Family Comprehensive Cancer Center

Rahul Aggarwal

UCSF Helen Diller Family Comprehensive Cancer Center

Eric Liu

In-Q-Tel

Eric J. Small

UCSF Helen Diller Family Comprehensive Cancer Center

Mark Bridge

UCSF Helen Diller Family Comprehensive Cancer Center

Eric D. Chow

University of California, San Francisco

Jaqueline Marquez

University of California, San Francisco

Cooperative Institutions

University of California, San Francisco

UCSF Helen Diller Family Comprehensive Cancer Center

The University of Texas Medical Branch at Galveston

Stanford University

Oregon Health & Science University

University of Wisconsin–Madison

The University of Texas Health Science Center at Houston

City College of San Francisco

The University of Texas at Austin

National Institutes of Health

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MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase

PLoS Pathogens (2016)

Huafeng Wang Mengyi Li Chiung-Yu Hung Meenal Sinha Linda M. Lee

Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells. The poor survival of activated T cells in Myd88-/- mice is linked to increased caspase3-mediated apoptosis, but not to Fas- or Bim-dependent apoptotic pathways, nor to reduced expression of the anti-apoptotic molecules Bcl-2 or Bcl-xL. Moreover, TLR3, 7, and/or 9, but not TLR2 or 4, also were required extrinsically for MyD88-dependent Th17 cell responses and vaccine immunity. Similar MyD88 requirements governed the survival of virus primed T cells. Our data identify unappreciated new requirements for eliciting adaptive immunity and have implications for designing vaccines.

TLR3

TLR7

10.1371/journal.ppat.1005787

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Citations (9)

The impact of prior radiation therapy on outcome in a phase 2 trial combining sipuleucel-T (SipT) and ipilimumab (Ipi) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).

Journal of Clinical Oncology (2021)

Li Zhang Meenal Sinha Sumit K. Subudhi Brandon Chen Jaqueline Marquez

5045 Background: SipT is an FDA-approved autologous cellular immunotherapy targeting Prostatic Acid Phosphatase (PAP) that improves survival in patients with mCRPC. Combining immunotherapies could provide opportunities to enhance efficacy. We performed a randomized phase II trial adding CTLA-4 blockade with Ipi following SipT treatment and assessed whether timing of this sequence could modify immune and/or clinical responses to this treatment. Methods: Fifty chemotherapy-naïve mCRPC pts were randomized to receive ipi (4 doses of 3mg/kg every 3 weeks) either immediately (n = 24) or 3 weeks (n = 26) following completion of sipT. Blood was collected at various time points of the study. Immune-related adverse events (irAE) were recorded. The primary endpoint was to determine the proportion of pts who achieved an antibody titer of ³1:400 to PA2024, the targeting cassette in SipT and/or PAP. Clinical response was defined as ³30% reduction in serum prostate specific antigen (PSA) compared to pre-treatment levels. Radiographic progression-free survival (rPFS) and overall survival (OS) were defined as from the date of randomization to the date of radiographic progression and the date of death, respectively, or last follow-up date. Luminex assays for anti-PAP and anti-PA2024 specific serum IgG and ELISpot for IFN-g production against PAP and PA2024 were used to assess antigen-specific B and T cells responses, respectively. Modulation of circulating immune cells was evaluated by CyTOF. Results: SipT + Ipi did not induce any unexpected irAEs. The timing of Ipi did not significantly alter the rates of clinical response, rPFS, OS, toxicity, nor antigen-specific B and T cell responses. Clinical responses were observed in 6 of 50 (12%) pts and were often durable (median 140 days, range 55-689 days). Pts experiencing irAEs were more likely to have a PSA response (P = 0.001). The median rPFS was 5.7 months (mos). The median OS was 31.9 mos. This treatment induced antibody and T cell immune responses irrespective of treatment arm. Single cell assessment bt CyTOF demonstrated that treatment induced CD4 and CD8 T cell activation that was more pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells were associated with better clinical outcomes even at baseline. Lower frequencies of CTLA-4 positive T cells was associated with prior radiation therapy. Prior radiation treatment was associated with improved rPFS (6.5 vs. 3.9 mos, P = 0.004). Conclusions: These findings suggest that pre-existing immunity may help dictate responsiveness to Ipi and SipT combination immunotherapy in mCRPC pts. Prior radiation therapy seems to leave not only a lasting impression on the T cell compartment, but also can associate with improved clinical outcomes with subsequent immunotherapy. Clinical trial information: NCT01804465.

ELISPOT

Prostatic acid phosphatase

Clinical endpoint

Surrogate endpoint

10.1200/jco.2021.39.15_suppl.5045

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Supplementary Table 1 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer

Hewitt Chang Jaqueline Marquez Brandon K. Chen Daniel M. Kim Michael L. Cheng

Characteristics of trial patients

Denosumab

Immune Modulation

Table (database)

10.1158/2326-6066.25540806

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Supplementary Figure 1 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer

Hewitt Chang Jaqueline Marquez Brandon K. Chen Daniel M. Kim Michael L. Cheng

Supplementary Figure 1: Manual gating strategy A representative patient sample was used to illustrate the gating strategy on Cytobank to create pre-determined landmark nodes for scaffold analysis and clustering.

Denosumab

Immune Modulation

10.1158/2326-6066.25523144.v1

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Immune modulatory effects of ibrutinib in pancreatic ductal adenocarcinoma

Annals of Oncology (2019)

Meenal Sinha Michael Griffith Courtney B. Betts Gina Choe Shamilene Sivagnanam

Regimen

10.1093/annonc/mdz155.145

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Supplementary Figure 5 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer

Hewitt Chang Jaqueline Marquez Brandon K. Chen Daniel M. Kim Michael L. Cheng

Supplementary Figure 5: Effects of concomitant treatments during denosumab treatment Heatmaps summarizing log2 fold changes from statistical analysis of functional markers CD137, CD27, CD40, CD40L, CD71, CD95, CTLA-4, HLA-DR, ICOS, Ki-67, NKG2D, OX40, PD-1, PD-L1, PD-L2, TIGIT and TIM3 when comparing (A) patients that received only chemotherapy or chemotherapy and steroids with patients that did not receive chemotherapy or steroids at pretreatment timepoint 1 (TP1) and post-treatment timepoints 2 and 3 (TP2 and TP3); (B) patients received only steroids with patients that received only chemotherapy or chemotherapy and steroids at TP2 and TP3; (C) patients that received only steroids with patients that did not receive chemotherapy or steroids at TP2 and TP3. Each box in the heatmap represents a lymphocyte cluster that was labeled according to the nearest landmark node they connect to on the scaffold map and ordered by cell count abundance. The pseudocolor represents clusters that showed a significant difference (q<0.05) in the log2 fold change, with red being significantly higher, while blue being significantly lower in group 2 of the two comparison groups.

Denosumab

Immune Modulation

10.1158/2326-6066.25540809.v1

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84 PATTERNS OF INTERFERON-INDUCED GENES IN LIVER AND PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) DURING THE FIRST 24 HOUR (PHASE 1) TREATMENT IN HCV GENOTYPE 1 PATIENTS

Journal of Hepatology (2009)

Daryl Lau Meenal Sinha Y. Zhang Emi Shudo A.S. Perelson

10.1016/s0168-8278(09)60086-6

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Supplementary Table 2 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer

Hewitt Chang Jaqueline Marquez Brandon K. Chen Daniel M. Kim Michael L. Cheng

Supplementary Table 2

Denosumab

Table (database)

Immune Modulation

10.1158/2326-6066.25523126.v1

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Supplementary Figure 4 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer

Hewitt Chang Jaqueline Marquez Brandon K. Chen Daniel M. Kim Michael L. Cheng

Supplementary Figure 4: Pre-existing immune condition prior to denosumab treatment Heatmaps summarizing log2 fold changes from statistical analysis of functional markers CD137, CD27, CD40, CD40L, CD71, CD95, CTLA-4, HLA-DR, ICOS, Ki-67, NKG2D, OX40, PD-1, PD-L1, PD-L2, TIGIT and TIM3 when comparing patients who did not receive chemotherapy or steroids with patients that received chemotherapy, steroids, or both at pretreatment TP1. Each box in the heatmap represents a lymphocyte cluster that was labeled according to the nearest landmark node they connect to on the scaffold map and ordered by cell count abundance. The pseudocolor represents clusters that showed a significant difference (q<0.05) in the log2 fold change, with red being significantly higher, while blue being significantly lower in group 2 of the two comparison groups.

Denosumab

Immune Modulation

Cancer Treatment

10.1158/2326-6066.25523135

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Inpatient Healthcare Resource Utilization (HCRU), Costs, and Mortality in Adult Patients with Steroid-Refractory Acute Graft-vs-Host Disease (SR aGVHD) Following Allogeneic Hematopoietic Stem Cell Transplant (a-HSCT)

Biology of Blood and Marrow Transplantation (2018)

Jingbo Yu Jennifer Judy Shreekant Parasuraman Meenal Sinha Ahmad Naim

Objectives: To describe inpatient HCRU, costs, and mortality in patients with SR aGVHD in the United States. Methods: A retrospective analysis was conducted using Premier Healthcare database. Adults discharged for first a-HSCT between 1/1/2011–6/30/2016 with a diagnosis of aGVHD (ICD-9 279.50, 279.51; ICD-10 D89.810, D89.813) were identified. Patients with SR aGVHD were defined as those who received ≥50 mg/d systemic steroids for ≥3 days during a-HSCT hospitalization or ≥1 day during readmission and also received second-line therapy during the same stay. Hospital length of stay (LOS), intensive care unit (ICU) admission, total hospital costs during both initial a-HSCT admission and readmissions, and inpatient mortality within 100 days of a-HSCT were reported for patients with no GVHD, and patients with SR aGVHD. Results: Patients in the analysis had a mean age of 51 years, were 42% female, and most (74%) received peripheral blood grafts. During a-HSCT admissions, patients with SR aGVHD had greater median LOS, ICU admission rates, median hospital costs, and mortality rates than patients without GVHD. Compared to no GVHD, patients with SR aGVHD had greater readmission rates, median readmission LOS and costs, and readmission mortality rates. 100-day inpatient mortality rates for patients with SR aGVHD was 4-fold that of no GVHD (Table 1).Table 1Inpatient HCRU, Costs, and Mortality During the First 100 Days of a-HSCT for Patients With No GVHD and SR aGVHD Conclusion: SR aGVHD is associated with substantial increases in HCRU, costs, and mortality. Over half of SR aGVHD patients required ICU admission, and over a third of SR aGVHD patients died in the hospital within 100 days of HSCT. Prevention or mitigation of SR aGVHD has the potential for substantial reductions in HCRU and mortality.

10.1016/j.bbmt.2017.12.144

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