Keith A. Ching

National University Heart Centre Singapore

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John J. Gaudino

Pfizer (United States)

Anurag Singh

Pfizer (United States)

Christina E. Wong

Pfizer (United States)

Nickolas A. Neitzel

Pfizer (United States)

Eric N. Brown

Pfizer (United States)

S. Michael Rothenberg

Pfizer (United States)

Micaela B. Reddy

Pfizer (United States)

Mohamed Elsayed

Pfizer (United States)

Yutong Jiang

Pfizer (United States)

Dale Nepert

Pfizer (United States)

Cooperative Institutions

Pfizer (United States)

188

Samsung Medical Center

University of California, San Diego

Harvard University

Dana-Farber Cancer Institute

Sungkyunkwan University

Stanford University

Scripps Research Institute

Erasmus MC

The University of Texas MD Anderson Cancer Center

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Data from PEST Domain Mutations in Notch Receptors Comprise an Oncogenic Driver Segment in Triple-Negative Breast Cancer Sensitive to a γ-Secretase Inhibitor

Kai Wang Qin Zhang Danan Li Keith A. Ching Cathy Zhang

<div>AbstractPurpose: To identify and characterize novel, activating mutations in Notch receptors in breast cancer and to determine response to the gamma secretase inhibitor (GSI) PF-03084014.Experimental Design: We used several computational approaches, including novel algorithms, to analyze next-generation sequencing data and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with PF-03084014. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by PF-03084014.Results: We identified mutations within and upstream of the PEST domains of NOTCH1, NOTCH2, and NOTCH3 in the TCGA dataset. Mutations occurred via several genetic mechanisms and compromised the function of the PEST domain, a negative regulatory domain commonly mutated in other cancers. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain mutations at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple-negative breast cancer subtype (TNBC). PDX models were also identified that harbored PEST domain mutations, and these models were highly sensitive to PF-03084014.Conclusions: This work suggests that Notch-altered breast cancer constitutes a bona fide oncogenic driver segment with the most common alteration being PEST domain mutations present in multiple Notch receptors. Importantly, functional studies suggest that this newly identified class can be targeted with Notch inhibitors, including GSIs. Clin Cancer Res; 21(6); 1487–96. ©2015 AACR.</div>

Triple-negative breast cancer

10.1158/1078-0432.c.6523893

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Data from First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas

Ajay K. Gopal Ronald Levy Roch Houot Sandip Pravin Patel Leslie Popplewell

<div>AbstractPurpose:In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20+ non-Hodgkin lymphomas (NHL).Patients and Methods:Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D).Results:Sixty-seven patients received utomilumab (0.03–10.0 mg/kg every 4 weeks) and rituximab (375 mg/m2 weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%–33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function.Conclusions:Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs.</div>

Follicular lymphoma

Tolerability

Pharmacodynamics

Refractory (planetary science)

10.1158/1078-0432.c.6529910

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Figure S6 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Alexander Drilon Manish R. Sharma Melissa L. Johnson Timothy A. Yap Shirish M. Gadgeel

Supplementary Figure 6: PK profiles for patients

Targeted Therapy

Solid tumor

10.1158/2159-8290.23291491.v1

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Figure S4 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Alexander Drilon Manish R. Sharma Melissa L. Johnson Timothy A. Yap Shirish M. Gadgeel

Supplementary Figure 4: PF-07284892 combination efficacy in additional oncogenic driver-positive mouse cancer models and monotherapy PK/PD

Targeted Therapy

Solid tumor

10.1158/2159-8290.23291497.v1

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Figure S5 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Alexander Drilon Manish R. Sharma Melissa L. Johnson Timothy A. Yap Shirish M. Gadgeel

Supplementary Figure 5: Study schema

Targeted Therapy

Solid tumor

10.1158/2159-8290.23291494.v1

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Table S2 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Alexander Drilon Manish R. Sharma Melissa L. Johnson Timothy A. Yap Shirish M. Gadgeel

Supplementary Table 2: Phosphatase Profiling of PF-07284892

Targeted Therapy

Table (database)

Profiling (computer programming)

Solid tumor

10.1158/2159-8290.23291479

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Supplementary Figure S1 from First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas

Ajay K. Gopal Ronald Levy Roch Houot Sandip Pravin Patel Leslie Popplewell

(A) Levels of soluble 4-1BB/CD137 and (B) changes in CD8+ T cells from Cycle 1 day 1, in individual patients by dose group.

CD137

10.1158/1078-0432.22478291

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An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity

Cancer Immunology Research (2021)

Yuanming Xu Lucia Campos Carrascosa Yik A. Yeung Matthew Ling-Hon Chu Wenjing Yang

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.

10.1158/2326-6066.cir-21-0058

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Table S4 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Alexander Drilon Manish R. Sharma Melissa L. Johnson Timothy A. Yap Shirish M. Gadgeel

Supplementary Table 4: Pharmacokinetics of PF-07284892 in preclinical species

Targeted Therapy

Solid tumor

Table (database)

10.1158/2159-8290.23853155

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