Publications by authors named "Cara Haymaker"

75 Publications

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

Clin Transl Med 2021 Jul;11(7):e491

Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.

Background: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR.

Methods: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed.

Results: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4 PD-1 cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4 CD25hi cells and CD69 expression on intermediate monocytes; but lower levels of CD3 CD56 CTLA-4 cells, CD14 CD16 CTLA-4 cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR.

Conclusions: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses.
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http://dx.doi.org/10.1002/ctm2.491DOI Listing
July 2021

Multi-Center Immune Profiling Mass Cytometry Assay Harmonization.

Clin Cancer Res 2021 Jul 15. Epub 2021 Jul 15.

Human Immune Monitoring Center, Icahn School of Medicine at Mt. Sinai.

Purpose: The Cancer Immune Monitoring and Analysis Centers - Cancer Immunologic Data Commons (CIMAC-CIDC) Network is supported by the National Cancer Institute to identify biomarkers of response to cancer immunotherapies across clinical trials using state-of-the-art assays. A primary platform for CIMAC-CIDC studies is cytometry by time-of-flight (CyTOF), performed at all CIMAC laboratories. To ensure the ability to generate comparable CyTOF data across labs, a multistep cross-site harmonization effort was undertaken.

Experimental Design: We first harmonized standard operating procedures (SOPs) across the CIMAC sites. Because of a new acquisition protocol comparing original narrow - or new wide bore injector introduced by the vendor (Fluidigm), we also tested this protocol across sites before finalizing the harmonized SOP. We then performed cross-site assay harmonization experiments using 5 shared cryopreserved and one lyophilized internal control PBMCs with a shared lyophilized antibody cocktail consisting of 14 isotype-tagged antibodies previously validated, plus additional liquid antibodies. These reagents and samples were distributed to the CIMAC sites and the data were centrally analyzed by manual gating and automated methods (Astrolabe).

Results: Average coefficients of variation (CVs) across sites for each cell population were reported and compared to a previous multisite CyTOF study. We reached an inter-site CV of under 20% for most cell subsets, similar to a previously published study.

Conclusions: These results establish the ability to reproduce CyTOF data across sites in multi-center clinical trials, and also highlight the importance of quality control procedures, such as the use of spike-in control samples, for tracking variability in this assay.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2052DOI Listing
July 2021

Pulmonary resection for tissue harvest in adoptive tumor-infiltrating lymphocyte therapy: Safety and feasibility.

J Surg Oncol 2021 May 31. Epub 2021 May 31.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background And Objectives: Adoptive T-cell therapies (ACTs) using expansion of tumor-infiltrating lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease.

Methods: Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications.

Results: 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days.

Conclusions: Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.
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http://dx.doi.org/10.1002/jso.26548DOI Listing
May 2021

Randomized phase II trial of lymphodepletion plus adoptive cell transfer of tumor-infiltrating lymphocytes, with or without dendritic cell vaccination, in patients with metastatic melanoma.

J Immunother Cancer 2021 May;9(5)

Melanoma Medical Onoclogy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen-loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses.

Design: We tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival.

Results: Ten patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8 TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated.

Conclusions: The combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups.

Trial Registration Number: NCT00338377.
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http://dx.doi.org/10.1136/jitc-2021-002449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144048PMC
May 2021

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features.

Nat Commun 2021 05 11;12(1):2722. Epub 2021 May 11.

Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
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http://dx.doi.org/10.1038/s41467-021-22890-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113327PMC
May 2021

Extrapleural Pneumonectomy versus Pleurectomy/Decortication for Malignant Pleural Mesothelioma.

Ann Thorac Surg 2021 May 7. Epub 2021 May 7.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: Whether extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D) is the optimal resection for malignant pleural mesothelioma (MPM) remains controversial. We therefore compared perioperative outcomes and long-term survival of patients who underwent EPP vs P/D.

Methods: Patients with the diagnosis of MPM who underwent either EPP or P/D from 2000 to 2019 were identified from our departmental database. Propensity score matching was performed to minimize potential confounders for EPP or P/D. Survival analysis was performed by the Kaplan-Meier method and Cox multivariable analysis.

Results: Of 282 patients, 187 (66%) underwent EPP and 95 (34%) P/D. Even with propensity score matching, perioperative mortality was significantly higher for EPP than for P/D (11% vs. 0%; P=0.031), when adjusted for perioperative mortality, median overall survival between EPP and P/D was 15 vs. 22 months, respectively (P=0.276). Cox multivariable analysis for the matched cohort identified epithelioid histology (hazard ratio [HR], 0.56; P=0.029), macroscopic complete resection (HR, 0.41; P=0.004), adjuvant radiation therapy (HR, 0.57; P=0.019), and more recent operative years (HR, 0.93; P=0.011)-but not P/D-to be associated with better survival. Asbestos exposure (HR, 2.35; P=0.003) and pathological nodal disease (HR, 1.61; P=0.048) were associated with worse survival.

Conclusions: In a multimodality treatment setting, P/D and EPP had comparable long-term oncological outcomes, although P/D had much lower perioperative mortality. The goal of surgical cytoreduction should be macroscopic complete resection achieved by the safest operation a patient can tolerate.
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.078DOI Listing
May 2021

Preclinical Development and First-in-Human Study of KA2507, a Selective and Potent Inhibitor of Histone Deacetylase 6, for Patients with Refractory Solid Tumors.

Clin Cancer Res 2021 Jul 4;27(13):3584-3594. Epub 2021 May 4.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor.

Patients And Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018).

Results: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, = 2; rectal adenocarcinoma, = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively.

Conclusions: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0238DOI Listing
July 2021

Immuno-profiling and cellular spatial analysis using five immune oncology multiplex immunofluorescence panels for paraffin tumor tissue.

Sci Rep 2021 Apr 19;11(1):8511. Epub 2021 Apr 19.

Department of Translational Molecular Pathology, Unit 951, The University of Texas MD Anderson Cancer Center, 2130 Holcombe Blvd., Houston, TX, 77030, USA.

Multiplex immunofluorescence (mIF) has arisen as an important tool for immuno-profiling tumor tissues. We updated our manual protocol into an automated protocol that allows the use of up to seven markers in five mIF panels to apply to formalin-fixed paraffin-embedded tumor tissues. Using a tyramide signal amplification system, we optimized five mIF panels that included cytokeratin to characterize malignant cells (MCs), immune checkpoint markers (i.e., PD-L1, B7-H3, B7-H4, IDO-1, VISTA, LAG3, ICOS, TIM3, and OX40), tumor-infiltrating lymphocytic markers (i.e., CD3, CD8, CD45RO, granzyme B, PD-1, and FOXP3), and markers to characterize myeloid-derived suppressor cells (i.e., CD68, CD66b, CD14, CD33, Arg-1, and CD11b). To determine analytical reproducibility and the impact of those panels for immuno-profiling tumor tissues, we performed an exploratory analysis in a set of non-small cell lung cancer (NSCLC) samples. The slides were scanned, and the different cell phenotypes were quantified by simultaneous co-localizations with the markers using image analysis software. Comparison between the time points of staining showed high analytical reproducibility. The analysis of NSCLC cases showed an immunosuppressive microenvironment with PD-L1/PD-1 expression as a predominant axis. Interestingly, high density of MCs expressing B7-H4 was correlated with recurrence. Unexpectedly, MCs expressing OX40 were also detected, and those cells were a closer distance to CD3+T-cells than were MCs expressing other immune checkpoints. Two different cellular patterns of spatial distribution were determined according the CD3 distribution, and the predominant pattern was related with active immunosuppressive interaction with MCs. Our study shows that these five mIF panels can identify multiple targets in a single cell with high reproducibility. The study of different cell populations and their spatial relationship can open new ideas for therapeutic approaches.
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http://dx.doi.org/10.1038/s41598-021-88156-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055659PMC
April 2021

Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases.

Clin Cancer Res 2021 Jun 2;27(11):3039-3049. Epub 2021 Apr 2.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti-CTLA-4 and an anti-PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting.

Patients And Methods: Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety.

Results: A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%-88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%-44%) and 2/17 (12%; 95% CI: 2%-38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1-17.8) months, and overall survival was 24.5 (95% CI: 16.5-28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8 and CD4 activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS.

Conclusions: This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172528PMC
June 2021

Identification of bacteria-derived HLA-bound peptides in melanoma.

Nature 2021 04 17;592(7852):138-143. Epub 2021 Mar 17.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

A variety of species of bacteria are known to colonize human tumours, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.
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http://dx.doi.org/10.1038/s41586-021-03368-8DOI Listing
April 2021

Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.

Cancer Discov 2021 Mar 11. Epub 2021 Mar 11.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1546DOI Listing
March 2021

Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues.

Sci Rep 2021 Feb 25;11(1):4530. Epub 2021 Feb 25.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Unit 9512130 Holcombe Blvd, Houston, TX, 77030, USA.

Immune profiling is becoming a vital tool for identifying predictive and prognostic markers for translational studies. The study of the tumor microenvironment (TME) in paraffin tumor tissues such as malignant pleural mesothelioma (MPM) could yield insights to actionable targets to improve patient outcome. Here, we optimized and tested a new immune-profiling method to characterize immune cell phenotypes in paraffin tissues and explore the co-localization and spatial distribution between the immune cells within the TME and the stromal or tumor compartments. Tonsil tissues and tissue microarray (TMA) were used to optimize an automated nine-color multiplex immunofluorescence (mIF) panel to study the TME using eight antibodies: PD-L1, PD-1, CD3, CD8, Foxp3, CD68, KI67, and pancytokeratin. To explore the potential role of the cells into the TME with this mIF panel we applied this panel in twelve MPM cases to assess the multiple cell phenotypes obtained from the image analysis and well as their spatial distribution in this cohort. We successful optimized and applied an automated nine-color mIF panel to explore a small set of MPM cases. Image analysis showed a high degree of cell phenotype diversity with immunosuppression patterns in the TME of the MPM cases. Mapping the geographic cell phenotype distribution in the TME, we were able to identify two distinct, complex immune landscapes characterized by specific patterns of cellular distribution as well as cell phenotype interactions with malignant cells. Successful we showed the optimization and reproducibility of our mIF panel and their incorporation for comprehensive TME immune profiling into translational studies that could refine our ability to correlate immunologic phenotypes with specific patterns of cells distribution and distance analysis. Overall, this will improve our ability to understand the behavior of cells within the TME and predict new treatment strategies to improve patient outcome.
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http://dx.doi.org/10.1038/s41598-021-83858-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907283PMC
February 2021

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Nat Med 2021 03 18;27(3):504-514. Epub 2021 Feb 18.

Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
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http://dx.doi.org/10.1038/s41591-020-01224-2DOI Listing
March 2021

Next-Generation Immunotherapies to Improve Anticancer Immunity.

Front Pharmacol 2020 11;11:566401. Epub 2021 Jan 11.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell-mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.
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http://dx.doi.org/10.3389/fphar.2020.566401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831045PMC
January 2021

Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target.

J Thorac Oncol 2021 04 31;16(4):583-600. Epub 2020 Dec 31.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood.

Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response.

Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth.

Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.12.010DOI Listing
April 2021

Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.

Cancer Immunol Immunother 2021 Apr 29;70(4):1101-1113. Epub 2020 Oct 29.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.
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http://dx.doi.org/10.1007/s00262-020-02748-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979613PMC
April 2021

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC.

J Thorac Oncol 2021 01 21;16(1):127-139. Epub 2020 Oct 21.

Biologics Development Department, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade.

Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73).

Results: NCT was associated with increased infiltration of cytotoxic CD8 T cells and CD20 B cells. Moreover, NCT was associated with increases in CD8CD103 and CD4CD103PD-1TIM3 tissue resident memory T cells. Gene expression profiling supported memory function of CD8 and CD4 T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery.

Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8 and CD4 memory helper T cells.
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http://dx.doi.org/10.1016/j.jtho.2020.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775914PMC
January 2021

T-cell agonists in cancer immunotherapy.

J Immunother Cancer 2020 10;8(2)

Section of Immunology, Department of Allergy & Rheumatology, Baylor College of Medicine, Texas and Texas Children's Hospital, Houston, Texas, USA.

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.
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http://dx.doi.org/10.1136/jitc-2020-000966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537335PMC
October 2020

Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment.

Clin Cancer Res 2020 10 14;26(20):5477-5486. Epub 2020 Aug 14.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.

Experimental Design: We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib.

Results: The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib-treated tumors had significantly longer survival.

Conclusions: Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709879PMC
October 2020

Peripheral cytokines are not influenced by the type of surgical approach for non-small cell lung cancer by four weeks postoperatively.

Lung Cancer 2020 08 27;146:303-309. Epub 2020 Jun 27.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, United States. Electronic address:

Objectives: The influence of surgical approach on systemic inflammatory response and the subsequent oncologic impact for non-small cell lung cancer is debated. We aimed to measure the effects of thoracic surgical approach on peripheral cytokine milieu over time.

Methods: Patients undergoing primary lung resection without neoadjuvant therapy (2016-2018) were evaluated. A panel of 43 cytokines, angiogenic factors, and inflammatory molecules (CAFs) were evaluated in peripheral blood preoperatively, at 24 -hs and 4-weeks postoperatively. Differences between CAFs in patients undergoing thoracotomy versus video-assisted thoracoscopic surgery (VATS) at all timepoints were assessed using Student's t-test.

Results: 76 patients with available peripheral CAF panels met inclusion criteria. Thoracotomy was performed in 53 (70 %) patients while VATS was undertaken in 23 (30 %). Upon examination of known inflammatory CAFs, including IL-1β, IL-6, IL-8, IL-10, IFN-γ, and soluble (s) CD27, no differences were detected at 24 h or 4 weeks postoperatively between surgical groups. Examination of trends over time did not demonstrate any temporal derangements for these CAFs, with return to baseline levels by 4 weeks postoperatively for both groups. Evaluation of soluble (s) checkpoint molecules, including sPD-1, sPD-L1, sTIM-3, and sCTLA-4, did not reveal any differences in the immediate postoperative or long-term recovery period.

Conclusions: Peripheral immune profiles following pulmonary resection do not appear to differ between VATS and thoracotomy postoperatively. CAF fluctuations are transient and recover rapidly. These results, at the peripheral cytokine level, suggest that the surgical approach for lung cancer is unlikely to alter the effectiveness of novel immune-modulating systemic therapies, although more studies are needed to validate these findings.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.022DOI Listing
August 2020

Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02).

Cancer Discov 2020 08 21;10(8):1158-1173. Epub 2020 May 21.

Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York.

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension ( = 1), hyperglycemia ( = 1), metabolic acidosis ( = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8 T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1510DOI Listing
August 2020

Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort.

J Immunother Cancer 2020 04;8(1)

Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: The biological underpinnings of the prognostic and predictive significance of a relative neutrophilia in patients with non-small lung cancer (NSCLC) are undefined. We sought to comprehensively examine the relationships between circulating and intratumoral neutrophil populations and features of the immune contexture in patients undergoing NSCLC resection.

Methods: Preoperative soluble cytokine and angiogenic factors; tumor multiplex immunofluorescence; RNA, whole exome, and T-cell receptor sequencing; and flow cytometry were analyzed for relationships with populations of circulating (from complete blood counts) and intratumoral neutrophils (transcriptional signatures) in a prospectively enrolled resected NSCLC cohort (n=66). In a historical cohort (n=1524), preoperative circulating neutrophil and lymphocyte counts were analyzed for associations with overall survival (OS).

Results: Circulating neutrophil populations were positively correlated with increased tumor burden, and surgical tumor resection was followed by a subsequent reduction in peripheral neutrophil counts. Expansion of the circulating neutrophil compartment was associated with increased levels of pro-granulopoietic (IL-1β, IL-17A, TNFα, IL-6) and T2-associated (IL-5, IL-13) cytokines. Tumors with high intratumoral neutrophil burden were marked by a blunted T-cell response characterized by reduced expression of cytotoxic T-cell genes (, , , ), decreased CD3CD8 cell infiltration, and diminished expression of IFNγ-related genes. The associations between increased intratumoral neutrophil burden and reduced CD3CD8 infiltration persisted after adjustment for tumor size, histology, mutational burden, and PD-L1 expression. In 1524 patients, elevated preoperative circulating neutrophil count was independently associated with worse OS (main effect HR 1.82, 95% CI 1.24 to 2.68, p=0.002).

Conclusions: Our findings demonstrate that neutrophil expansion reflects protumorigenic and immunosuppressive processes that manifest as worse OS in patients undergoing NSCLC resection. These results justify further investigation of therapeutic strategies targeting neutrophil-associated immune evasion.
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http://dx.doi.org/10.1136/jitc-2019-000405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213906PMC
April 2020

Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8 T Cells to Memory T Cells.

Cancer Immunol Res 2020 06 25;8(6):794-805. Epub 2020 Mar 25.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Clinical response rates after adoptive cell therapy (ACT) are highly correlated with persistence of the infused T cells. However, antigen-specific T cells found in tumor sites are often well-differentiated effector cells with limited persistence. Central memory CD8 T cells, capable of self-renewal, represent desirable ACT products. We report here that exposure to a histone deacetylase inhibitor (HDACi) and IL21 could reprogram differentiated human CD8 T cells into central memory-like T cells. Dedifferentiation of CD8 T cells was initiated by increased H3 acetylation and chromatin accessibility at the promoter region. This led to IL21-mediated pSTAT3 binding to the region, and subsequent upregulation of surface CD28 and CD62L (markers of central memory T cells). The reprogrammed cells exhibited enhanced proliferation in response to both IL2 and IL15, and a stable memory-associated transcriptional signature (increased and ). Our findings support the application of IL21 and HDACi for the generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269845PMC
June 2020

Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

Nat Commun 2020 01 31;11(1):661. Epub 2020 Jan 31.

Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8 T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8 Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.
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http://dx.doi.org/10.1038/s41467-020-14471-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994577PMC
January 2020

Procedural Requirements and Recommendations for Multiplex Immunofluorescence Tyramide Signal Amplification Assays to Support Translational Oncology Studies.

Cancers (Basel) 2020 Jan 21;12(2). Epub 2020 Jan 21.

Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

In the development of a multiplex immunofluorescence (IF) platform and the optimization and validation of new multiplex IF panels using a tyramide signal amplification system, several technical requirements are important for high-quality staining, analysis, and results. The aim of this review is to discuss the basic requirements for performing multiplex IF tyramide signal amplification (TSA) in formalin-fixed, paraffin-embedded cancer tissues to support translational oncology research. Our laboratory has stained approximately 4000 formalin-fixed, paraffin-embedded tumor samples using the multiplex IF TSA system for immune profiling of several labeled biomarkers in a single slide to elucidate cancer biology at a protein level and identify therapeutic targets and biomarkers. By analyzing several proteins in thousands of cells on a single slide, this technique provides a systems-level view of various processes in various tumor tissues. Although this technology shows high flexibility in cancer studies, it presents several challenges when applied to study different histology cancers. Our experience shows that adequate antibody validation, staining optimization, analysis strategies, and data generation are important steps for generating quality results. Tissue management, fixation procedures, storage, and cutting can also affect the results of the assay and must be standardized. Overall, this method is reliable for supporting translational research given a precise, step-by-step approach.
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http://dx.doi.org/10.3390/cancers12020255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072187PMC
January 2020

Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy.

Cancer Immunol Immunother 2019 Nov 10;68(11):1747-1757. Epub 2019 Oct 10.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (UT MDACC), Unit 904, 7455 Fannin, Houston, TX, 77054, USA.

Background: Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method.

Methods: TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT.

Results: Ovarian cancer is highly infiltrated with CD8 TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 10 cells in 2-3 weeks without over differentiation. In addition, the CD8 TIL grown with this method showed HLA-restricted tumor recognition.

Conclusions: These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.
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http://dx.doi.org/10.1007/s00262-019-02402-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269372PMC
November 2019

Exposure to anti-PD-1 causes functional differences in tumor-infiltrating lymphocytes in rare solid tumors.

Eur J Immunol 2019 12 30;49(12):2245-2251. Epub 2019 Sep 30.

Department of Investigational Therapeutics, The University of Texas MDACC, Houston, TX.

The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD-1) to boost anti-tumor immunity has positioned this approach to become the standard-of-care for some solid tumor malignancies. However, little is known as to how blockade of PD-1 may alter the function or phenotype of tumor-infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti-PD-1 (15-21 days post-dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8 and CD4 TIL populations. An enriched CTLA-4 expression in the CD4 TIL population was observed in TIL expanded from the on-treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on-treatment. The CD8 TIL population demonstrated a diminished cytokine secretion profile post-pembrolizumab. Overall, our study assesses the ramifications of one dose of anti-PD-1 on TIL in rare solid tumor types.
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http://dx.doi.org/10.1002/eji.201948217DOI Listing
December 2019

A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.

Cancer Discov 2019 06 15;9(6):711-721. Epub 2019 Apr 15.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8 T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1495DOI Listing
June 2019

TIL therapy and anti-CTLA4: can they co-exist?

Oncotarget 2019 Jan 1;10(1):1-2. Epub 2019 Jan 1.

Chantale Bernatchez: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MDACC, Houston, TX, USA.

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http://dx.doi.org/10.18632/oncotarget.26509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343756PMC
January 2019

Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer: A Phase 2 Clinical Trial.

JAMA Oncol 2019 01;5(1):67-73

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.

Importance: In recurrent human papilloma virus (HPV)-driven cancer, immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer.

Objective: To determine whether the efficacy of nivolumab, an anti-PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer.

Design, Setting, And Participants: In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16-positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017.

Interventions: The vaccine ISA101, 100 μg/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year.

Main Outcomes And Measures: Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1).

Results: Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy.

Conclusions And Relevance: The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study.

Trial Registration: ClinicalTrials.gov identifier: NCT02426892.
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http://dx.doi.org/10.1001/jamaoncol.2018.4051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439768PMC
January 2019
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