Publications by authors named "Adham S Bear"

10 Publications

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Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting.

Nat Commun 2021 07 16;12(1):4365. Epub 2021 Jul 16.

Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαβ isolation. TCR transfer to primary CD8 T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8 T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.
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http://dx.doi.org/10.1038/s41467-021-24562-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285372PMC
July 2021

Adoptive Cellular Therapy for Solid Tumors.

Am Soc Clin Oncol Educ Book 2021 Mar;41:57-65

Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Cancer immunotherapy tools include antibodies, vaccines, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies. This review will focus on adoptive cellular therapy, which involves the isolation of a patient's own immune cells followed by their ex vivo expansion and reinfusion. The majority of adoptive cellular therapy strategies utilize T cells isolated from tumor or peripheral blood, but may utilize other immune cell subsets. T-cell therapies in the form of tumor-infiltrating lymphocytes, T-cell receptor T cells, and CAR T cells may act as "living drugs" as these infused cells expand, engraft, and persist in vivo, allowing adaptability over time and enabling durable remissions in subsets of patients. Adoptive cellular therapy has been less successful in the management of solid tumors because of poor homing, proliferation, and survival of transferred cells. Strategies are discussed, including expression of transgenes to address these hurdles. Additionally, advances in gene editing using CRISPR/Cas9 and similar technologies are described, which allow for clinically translatable gene-editing strategies to enhance the antitumor activity and to surmount the hostilities advanced by the host and the tumor. Finally, the common toxicities and approaches to mitigate these are reviewed.
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http://dx.doi.org/10.1200/EDBK_321115DOI Listing
March 2021

Tumor-Derived Myeloid Cell Chemoattractants and T Cell Exclusion in Pancreatic Cancer.

Front Immunol 2020 10;11:605619. Epub 2020 Nov 10.

Abramson Cancer Center, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Like many tumor types, pancreatic ductal adenocarcinoma (PDAC) exhibits a rich network of tumor-derived cytokines and chemokines that drive recruitment of myeloid cells to the tumor microenvironment (TME). These cells, which include tumor-associated macrophages and myeloid derived suppressor cells, block the recruitment and priming of T cells, resulting in T cell exclusion within the TME. Genetic or pharmacologic disruption of this chemokine/cytokine network reliably converts the PDAC TME to a T cell-high phenotype and sensitizes tumors to immunotherapy across multiple preclinical models. Thus, neutralization of tumor-derived chemokines/cytokines or blockade of their respective receptors represents a potentially potent strategy to reverse myeloid immunosuppression in PDAC, enabling benefit from checkpoint inhibition not otherwise achievable in this disease. Inhibition of oncogenic pathways that drive tumor-intrinsic expression of chemoattractants may be similarly effective.
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http://dx.doi.org/10.3389/fimmu.2020.605619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693439PMC
June 2021

Challenges and Opportunities for Pancreatic Cancer Immunotherapy.

Cancer Cell 2020 12 17;38(6):788-802. Epub 2020 Sep 17.

Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDA) is among the most immune-resistant tumor types. Its unique genomic landscape shaped by oncogenic drivers promotes immune suppression from the earliest stages of tumor inception to subvert adaptive T cell immunity. Single-agent immune modulators have thus far proven clinically ineffective, and multi-modal therapies targeting mechanisms of immunotherapy resistance are likely needed. Here, we review novel immunotherapy strategies currently under investigation to (1) confer antigen specificity, (2) enhance T cell effector function, and (3) neutralize immunosuppressive elements within the tumor microenvironment that may be rationally combined to untangle the web of immune resistance in PDA and other tumors.
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http://dx.doi.org/10.1016/j.ccell.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738380PMC
December 2020

Low rate of infusional toxicity after expanded cord blood transplantation.

Cytotherapy 2014 Aug 28;16(8):1153-7. Epub 2014 Feb 28.

Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA.

Background Aims: Umbilical cord blood (CB) is used with increasing frequency to restore hematopoiesis in patients with bone marrow transplant who lack a suitable human leukocyte antigen-matched donor. CB transplantation is limited by low cell doses and delays in neutrophil and platelet engraftment. CB progenitors expanded ex vivo before transplantation provide more rapid hematopoietic and immune reconstitution as well as less engraftment failure compared with unmanipulated CB. However, the safety of infusing double and ex vivo-expanded CB has not been systematically examined.

Methods: We reviewed the immediate adverse events (AE) associated with the infusion of CB occurring within 24 hours in 137 patients enrolled in clinical CB transplant trials at the MD Anderson Cancer Center from February 2004 to May 2010. All patients received an unmanipulated CB unit followed by infusion of a second unmanipulated CB unit or a second CB unit expanded ex vivo with the use of cytokines in a liquid culture system or in mesenchymal stromal cell co-cultures.

Results: A total of three grade 2 and two grade 3 infusion reactions occurred within 24 hours of CB transplantation. This resulted in an AE rate of 3.7%. The majority of AEs manifested as signs of hypertension. No association with patient age, sex, disease status, premedication, ABO compatibility or total infusion volume was observed. In summary, the incidence of infusion-related toxicities in patients who receive unmanipulated and ex vivo-expanded double CB transplantation is low.

Conclusions: We conclude that the infusion of unmanipulated followed by expanded CB products is a safe procedure associated with a low probability of inducing severe reactions.
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http://dx.doi.org/10.1016/j.jcyt.2013.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087060PMC
August 2014

Elimination of metastatic melanoma using gold nanoshell-enabled photothermal therapy and adoptive T cell transfer.

PLoS One 2013 23;8(7):e69073. Epub 2013 Jul 23.

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Houston, Texas, United States of America.

Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b(+)Ly-6G/C(+) myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720863PMC
March 2014

An adaptable system for improving transposon-based gene expression in vivo via transient transgene repression.

FASEB J 2013 Sep 10;27(9):3753-62. Epub 2013 Jun 10.

Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA.

Transposons permit permanent cellular genome engineering in vivo. However, transgene expression falls rapidly postdelivery due to a variety of mechanisms, including immune responses. We hypothesized that delaying initial transgene expression would improve long-term transgene expression by using an engineered piggyBac transposon system that can regulate expression. We found that a 2-part nonviral Tet-KRAB inducible expression system repressed expression of a luciferase reporter in vitro. However, we also observed nonspecific promoter-independent repression. Thus, to achieve temporary transgene repression after gene delivery in vivo, we utilized a nonintegrating version of the repressor plasmid while the gene of interest was delivered in an integrating piggyBac transposon vector. When we delivered the luciferase transposon and repressor to immunocompetent mice by hydrodynamic injection, initial luciferase expression was repressed by 2 orders of magnitude. When luciferase expression was followed long term in vivo, we found that expression was increased >200-fold compared to mice that received only the luciferase transposon and piggyBac transposase. We found that repression of early transgene expression could prevent the priming of luciferase-specific T cells in vivo. Therefore, transient transgene repression postgene delivery is an effective strategy for inhibiting the antitransgene immune response and improving long-term expression in vivo without using immunosuppression.
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http://dx.doi.org/10.1096/fj.13-232090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752539PMC
September 2013

T cells as vehicles for cancer vaccination.

J Biomed Biotechnol 2011 27;2011:417403. Epub 2011 Oct 27.

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA.

The success of cancer vaccines is dependent on the delivery of tumor-associated antigens (TAAs) within lymphoid tissue in the context of costimulatory molecules and immune stimulatory cytokines. Dendritic cells (DCs) are commonly utilized to elicit antitumor immune responses due to their attractive costimulatory molecule and cytokine expression profile. However, the efficacy of DC-based vaccines is limited by the poor viability and lymph-node migration of exogenously generated DCs in vivo. Alternatively, adoptively transferred T cells persist for long periods of time in vivo and readily migrate between the lymphoid and vascular compartments. In addition, T cells may be genetically modified to express both TAA and DC-activating molecules, suggesting that T cells may be ideal candidates to serve as cellular vehicles for antigen delivery to lymph node-resident DCs in vivo. This paper discusses the concept of using T cells to induce tumor-specific immunity for vaccination against cancer.
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http://dx.doi.org/10.1155/2011/417403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205726PMC
March 2012

T cells enhance gold nanoparticle delivery to tumors in vivo.

Nanoscale Res Lett 2011 Apr 4;6(1):283. Epub 2011 Apr 4.

Department of Bioengineering, Rice University, Houston, TX 77005, USA.

Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.
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http://dx.doi.org/10.1186/1556-276X-6-283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3211348PMC
April 2011
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