Cancer Immunology Research Research Articles

Priming the pancreatic cancer tumor microenvironment for checkpoint-inhibitor immunotherapy

Single agent immunotherapy is effective against several cancers, but has failed against poorly immunogenic cancers, including pancreatic cancer. Evaluation of pancreatic tumors following treatment with an experimental vaccine (Lutz et al. Cancer Immunology Research 2014) suggests that vaccination primes the tumor microenvironment (TME) for checkpoint-inhibitor immunotherapy, and supports a new platform for evaluating checkpoint-inhibitors in poorly immunogenic cancers.

A New Cancer Immunology Research Special Feature: Perspective from a Master of Immunology

![Figure][1] Immune checkpoint blockade and adoptive T-cell therapy are transforming the landscape of cancer medicine and research. Blocking mAbs against the negative T-cell costimulatory molecules cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) and programmed death 1 (PD-1; or its

Modeling cancer-immune responses to therapy.

Cancer therapies that harness the actions of the immune response, such as targeted monoclonal antibody treatments and therapeutic vaccines, are relatively new and promising in the landscape of cancer treatment options. Mathematical modeling and simulation of immune-modifying therapies can help to offset the costs of drug discovery and development, and encourage progress toward new immunotherapies. Despite advances in cancer immunology research, questions such as how the immune system interacts with a growing tumor, and which components of the immune system play significant roles in responding to immunotherapy are still not well understood. Mathematical modeling and simulation are powerful tools that provide an analytical framework in which to address such questions. A quantitative understanding of the kinetics of the immune response to treatment is crucial in designing treatment strategies, such as dosing, timing, and predicting the response to a specific treatment. These models can be used both descriptively and predictively. In this chapter, various mathematical models that address different cancer treatments, including cytotoxic chemotherapy, immunotherapy, and combinations of both treatments, are presented. The aim of this chapter is to highlight the importance of mathematical modeling and simulation in the design of immunotherapy protocols for cancer treatment. The results demonstrate the power of these approaches in explaining determinants that are fundamental to cancer-immune dynamics, therapeutic success, and the development of efficient therapies.

Phenotypic T Cell Exhaustion in a Murine Model of Bacterial Infection in the Setting of Pre-Existing Malignancy

While much of cancer immunology research has focused on anti-tumor immunity both systemically and within the tumor microenvironment, little is known about the impact of pre-existing malignancy on pathogen-specific immune responses. Here, we sought to characterize the antigen-specific CD8+ T cell response following a bacterial infection in the setting of pre-existing pancreatic adenocarcinoma. Mice with established subcutaneous pancreatic adenocarcinomas were infected with Listeria monocytogenes, and antigen-specific CD8+ T cell responses were compared to those in control mice without cancer. While the kinetics and magnitude of antigen-specific CD8+ T cell expansion and accumulation was comparable between the cancer and non-cancer groups, bacterial antigen-specific CD8+ T cells and total CD4+ and CD8+ T cells in cancer mice exhibited increased expression of the coinhibitory receptors BTLA, PD-1, and 2B4. Furthermore, increased inhibitory receptor expression was associated with reduced IFN-γ and increased IL-2 production by bacterial antigen-specific CD8+ T cells in the cancer group. Taken together, these data suggest that cancer's immune suppressive effects are not limited to the tumor microenvironment, but that pre-existing malignancy induces phenotypic exhaustion in T cells by increasing expression of coinhibitory receptors and may impair pathogen-specific CD8+ T cell functionality and differentiation.

The immune system and head and neck squamous cell carcinoma: from carcinogenesis to new therapeutic opportunities

Head and neck squamous cell carcinomas (HNSCCs) exhibit complex interactions with the host immune system that may simultaneously explain resistance to various therapeutic modalities and that may also provide opportunities for therapeutic intervention. Discoveries in immunologic research over the last decade have led to an increased understanding of these interactions as well as the development of a multitude of investigational immunotherapies. Here, we describe the interaction between HNSCC and the immune system, including a discussion of immune cells involved with tumor carcinogenesis and the role of immune-modulating factors derived from tumors. We also describe the current immunotherapeutic approaches being investigated for HNSCC, including a discussion of the successes and limitations. With this review, we hope to present HNSCC as a model to guide future research in cancer immunology.

An exciting collaboration between AACR and CRI.

In concert with this first issue of Cancer Immunology Research, the American Association for Cancer Research (AACR) and the Cancer Research Institute (CRI) are pleased to announce a new collaboration between the organizations. The collaboration will involve sharing editorial resources as well as devoting a portion of the content of Cancer Immunology Research to CRI-related events and activities.Since its inception 60 years ago, CRI has been a major driver of progress in cancer immunology and immunotherapy. The late Dr. Lloyd J. Old served as CRI′s leader for much of this time, and he emphasized the importance of maintaining the highest level of intellectual rigor and creativity in approaching the fundamental issues of the antitumor host response. Dr. Old envisioned that detailed, complementary studies in experimental tumor models and cancer patients would, in the fullness of time, yield efficacious and broadly active immunotherapies. The recent clinical successes of anti-CTLA-4 and anti-PD-1/L1 monoclonal antibodies, adoptive T-cell therapy, and cancer vaccines suggest that the promise of investing in basic and translational research in cancer immunology is now coming to fruition.In addition to funding investigations in cancer immunology and immunotherapy, CRI, along with the Academy of Cancer Immunology, launched an important new journal, Cancer Immunity, in 2001. At the time, Cancer Immunity was the only journal devoted to all aspects of cancer immunology, and Dr. Old was its first Editor-in-Chief. In the ensuing years, Cancer Immunity has disseminated many types of influential scientific content important to cancer immunologists, including original research articles, reviews, hypotheses, case reports, and conference proceedings. Dr. James P. Allison, the current Editor-in-Chief, notes, “Cancer Immunity served a critical role at a time when efforts in cancer immunology and immunotherapy had not yet entered the mainstream of cancer research. The work of the journal emphasized the commitment of CRI and Lloyd Old to accelerating progress in the field.” Cancer Immunity will publish its final issue this month, and the editors of Cancer Immunology Research would like to take this opportunity to acknowledge its significant contributions to the field.The collaboration between AACR and CRI will be proudly shown on the cover and masthead of each issue of Cancer Immunology Research, and Dr. Allison has agreed to serve as a Deputy Editor. The Cancer Immunity content from all past issues will be relocated to the Cancer Immunology Research online journal site, allowing readers additional access to preeminent cancer immunology content in one location.This exciting undertaking will further accelerate progress in cancer immunology and immunotherapy. By coupling the longstanding commitment of CRI to tumor immunology with the breadth and depth of the AACR investment in all aspects of cancer biology and medicine, Cancer Immunology Research will serve as a link between immunology and the larger cancer research community. Dr. Glenn Dranoff, Founding Editor-in-Chief of Cancer Immunology Research, states, “The AACR–CRI collaboration builds upon the vision of Lloyd Old to bring to the benefit of cancer patients the best basic science possible and the most informative clinical trials. Through fostering productive interactions among academic investigators, industry, and patient advocates, Cancer Immunology Research will help to accelerate the control and prevention of cancer through effective manipulation of antitumor immunity.”

A Message from the Founding Editor-in-Chief

![Figure][1] This is an auspicious time for the AACR to launch Cancer Immunology Research , a new journal devoted to cancer immunology and immunotherapy. Recent clinical investigations have convincingly established that the immune system can be triggered to accomplish meaningful tumor

Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer

Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH) immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN). In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy.

Development of Tumor-Infiltrating CD8+ T Cell Memory Precursor Effector Cells and Antimelanoma Memory Responses Are the Result of Vaccination and TGF-β Blockade during the Perioperative Period of Tumor Resection

A main goal of cancer immunology research is the formation of Ag-specific memory T cell immunity capable of activation upon tumor re-encounter. The requirements necessary to overcome the inhibitory signals present in the tumor microenvironment and form such memory T cell responses are unknown. In contrast to previous studies targeting tumors expressing highly immunogenic model Ags, we demonstrate that alleviating tumor-induced suppression along with vaccination against authentic Ags during the perioperative period provides long-lasting protection against a highly suppressive and poorly immunogenic melanoma. In this study, we employed DNA vaccination with an immunologically optimized mouse melanoma-shared Ag, Trp1ee/ng, combined with systemic TGF-β blockade during the perioperative period of primary tumor resection, to confer protection against B16 melanoma, and against JBRH, an independently derived melanoma unrelated to B16. Importantly, we demonstrate that correlative to memory responses, perioperative immunotherapy increases the formation of tumor-infiltrating and tumor-reactive CD8(+) T cells expressing low levels of the transcription factor T-bet, defined as memory precursor effector cells. We show that conditions for an immunologically fertile environment are met when TGF-β blockade and vaccination are applied during the perioperative period of primary tumor resection. These findings address limitations of current CD8(+) T cell immunotherapies against cancer by generating effective CD8(+) T cell memory recall responses.

Malignant Gliomas: New Translational Therapies

Malignant gliomas are the most common primary brain tumors in adults and carry a dismal prognosis. Despite aggressive therapy with maximal safe surgical resection, radiation and chemotherapy, these tumors invariably are refractory to or become resistant to treatment and recur. Gliomas are highly infiltrative cancers and display remarkable genetic heterogeneity making them challenging to treat. Recent progress has been made in understanding the molecular and genetic composition of these tumors and from this, promising new targets for therapy have emerged. In particular, anti-angiogenesis therapies have led to modest success in disease control. In addition, the growing body of research in cancer immunology as well as cancer stem cells has made inroads in our understanding of tumorgenesis. Translational research has been particularly crucial to the development of these therapies as much preclinical and clinical work is needed to develop the rationale for treatments, to develop biomarkers of drug activity and to elucidate mechanisms of resistance. This brief overview will discuss some of the pivotal advances made in the pursuit of improved outcomes and survival for patients with this devastating disease.

Do CARs Need a Driver's License? Adoptive Cell Therapy with Chimeric Antigen Receptor-Redirected T Cells Has Caused Serious Adverse Events

Human Gene TherapyVol. 21, No. 9 CommentaryDo CARs Need a Driver's License? Adoptive Cell Therapy with Chimeric Antigen Receptor-Redirected T Cells Has Caused Serious Adverse EventsHildegard Büning, Wolfgang Uckert, Klaus Cichutek, Robert E. Hawkins, and Hinrich AbkenHildegard BüningZentrum für Molekulare Medizin Köln and Klinik I für Innere Medizin, Uniklinik Köln, D-50937 Cologne, Germany.Search for more papers by this author, Wolfgang UckertMax-Delbrück-Centrum für Molekulare Medizin, D-13125 Berlin-Buch, Germany.Search for more papers by this author, Klaus CichutekPaul Ehrlich Institut, D-63225 Langen, Germany.Search for more papers by this author, Robert E. HawkinsDepartment of Medical Oncology, Paterson Institute of Cancer Research, University of Manchester, Manchester, M20 4BX, UK.Search for more papers by this author, and Hinrich AbkenZentrum für Molekulare Medizin Köln and Klinik I für Innere Medizin, Uniklinik Köln, D-50937 Cologne, Germany.Search for more papers by this authorPublished Online:30 Jul 2010https://doi.org/10.1089/hum.2010.131AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited ByIn Vitro Engineering Chimeric Antigen Receptor Macrophages and T Cells by Lipid Nanoparticle-Mediated mRNA Delivery1 February 2022 | ACS Biomaterials Science & Engineering, Vol. 8, No. 2Ionizable Lipid Nanoparticle-Mediated mRNA Delivery for Human CAR T Cell Engineering17 January 2020 | Nano Letters, Vol. 20, No. 3Recent advances in tumor associated carbohydrate antigen based chimeric antigen receptor T cells and bispecific antibodies for anti-cancer immunotherapySeminars in ImmunologyCurrent Perspectives in Cancer Immunotherapy30 September 2019 | Cancers, Vol. 11, No. 10Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models2 August 2017 | Frontiers in Immunology, Vol. 8Bifunctional αHER2/CD3 RNA-engineered CART-like human T cells specifically eliminate HER2+ gastric cancer24 June 2016 | Cell Research, Vol. 26, No. 7Coexpressed Catalase Protects Chimeric Antigen Receptor–Redirected T Cells as well as Bystander Cells from Oxidative Stress–Induced Loss of Antitumor Activity16 December 2015 | The Journal of Immunology, Vol. 196, No. 2Rigorous optimization and validation of potent RNA CAR T cell therapy for the treatment of common epithelial cancers expressing folate receptor2 September 2015 | Oncotarget, Vol. 6, No. 30Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas22 January 2015 | OncoImmunology, Vol. 4, No. 3Dielectrophoresis-assisted 3D nanoelectroporation for non-viral cell transfection in adoptive immunotherapy1 January 2015 | Lab on a Chip, Vol. 15, No. 15Nature of Tumor Control by Permanently and Transiently Modified GD2 Chimeric Antigen Receptor T Cells in Xenograft Models of Neuroblastoma2 November 2014 | Cancer Immunology Research, Vol. 2, No. 11A closer look at chimeric antigen receptor specificityCytotherapy, Vol. 16, No. 10Engineered T cells for cancer treatmentCytotherapy, Vol. 16, No. 6Is cancer gene therapy an empty suit?The Lancet Oncology, Vol. 14, No. 11Cellular Immunotherapy for Carcinoma Using Genetically Modified EGFR-Specific T LymphocytesNeoplasia, Vol. 15, No. 5Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling17 April 2012 | Journal of Clinical Immunology, Vol. 32, No. 5A caspase 8-based suicide switch induces apoptosis in nanobody-directed chimeric receptor expressing T cells11 March 2012 | International Journal of Hematology, Vol. 95, No. 4Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses1 December 2011 | Cancer Immunology, Immunotherapy, Vol. 61, No. 1Cancer Immunotherapy Comes of AgeJournal of Clinical Oncology, Vol. 29, No. 36Treatment of Advanced Leukemia in Mice with mRNA Engineered T Cells David M. Barrett, Yangbing Zhao, Xiaojun Liu, Shuguang Jiang, Carmine Carpenito, Michael Kalos, Richard G. Carroll, Carl H. June, and Stephan A. Grupp12 August 2011 | Human Gene Therapy, Vol. 22, No. 12Transiently redirected T cells for adoptive transferCytotherapy, Vol. 13, No. 5Targeted cytotoxic therapy: adapting a rapidly progressing anticancer paradigm for depletion of persistent HIV-infected cell reservoirsCurrent Opinion in HIV and AIDS, Vol. 6, No. 1Multiple Injections of Electroporated Autologous T Cells Expressing a Chimeric Antigen Receptor Mediate Regression of Human Disseminated Tumor14 November 2010 | Cancer Research, Vol. 70, No. 22Can Engineered “Designer” T Cells Outsmart Chronic Hepatitis B?Hepatitis Research and Treatment, Vol. 2010 Volume 21Issue 9Sep 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:Hildegard Büning, Wolfgang Uckert, Klaus Cichutek, Robert E. Hawkins, and Hinrich Abken.Do CARs Need a Driver's License? Adoptive Cell Therapy with Chimeric Antigen Receptor-Redirected T Cells Has Caused Serious Adverse Events.Human Gene Therapy.Sep 2010.1039-1042.http://doi.org/10.1089/hum.2010.131Online Ahead of Print:August 2, 2010Published in Volume: 21 Issue 9: July 30, 2010Online Ahead of Editing: July 14, 2010PDF download

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis.

Cervical cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Objectives Gene expression profiling by microarrays is used to identify biomarkers predictive of the observed clinical activity of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) recorded in a Phase II study in metastatic melanoma (EORTC 16032-18031). Clinical activity to MAGE-A3 ASCI treatment in metastatic melanoma patients and a gene signature discriminating between clinical benefit and non clinical benefit patients were previously demonstrated (ASCO 2008). The predictive signature improved significantly the median time to treatment failure (2.3 months in the GS (-) and 10.3 months in the GS (+) population. Here we report on a new improved classifier to select patients with a higher likelihood of clinical response to treatment. Methods 75 patients with progressive, unresectable stage III or stage IV M1a MAGEA3 (+) melanomas, were randomized as 1st line therapy between immunization with MAGE-A3 recombinant protein combined with GSK Adjuvant Systems AS15 or AS02B. Gene expression profiling was performed on tumor biopsies taken prior to any immunization. Results Supervised classification experiments were conducted on a subset of 62 patients. A multivariate gene selection process was embedded in the estimation of a mathematical predictive model (linear support vector machine). Using bootstrap resamplings, gene selection was repeated on 30 independent sample sets. A final gene signature of 33 probes was derived from genes appearing most frequently after the various resamplings. The vast majority of the identified genes are immune-related. The final classifier correctly predicts clinical response with 91% sensitivity, 95% specificity and 91% positive predictive value. These performances were estimated on new independent resamplings of the same data. Conclusions The gene signatures found in metastatic melanoma patients are strongly correlated with the response to the MAGE-A3 ASCI treatment, reflecting an immune microenvironment in the tumor present prior to any therapeutic intervention. Such signatures and associated classifier could be used to select patients with a higher likelihood of response to MAGE-A3 ASCI treatment. This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.

From Breast Cancer Immunobiology to Her-2 DNA Vaccine and Autoimmune Sequelae

The heterogeneous nature of breast cancer and the correlation of myeloid cell infiltration with accelerated tumor progression were recognized early in breast cancer immunology research using murine model systems induced by the mouse mammary tumor virus, chemical carcinogens or hormones. Distinct cell lines established from a single mammary tumor attest to the challenges of controlling tumors with such complexity. Here, we test the feasibility of controlling breast cancer by active vaccination targeting a shared tumor-associated antigen, human ErB-2 (Her-2). Her-2 DNA vaccines were constructed and Her-2 transgenic mice were established. DNA vaccination overcomes Her-2 tolerance to induce anti-tumor immunity which is amplified by the removal of regulatory T cells, but is accompanied by a significant risk of autoimmunity. Her-2 vaccines combined with appropriate immune modulation to trigger in vivo priming to other tumor-associated antigens will be the key to improved breast cancer control.

The European Searchable Tumour Cell and Databank, ESTDAB, as a tool for research in cancer immunology

The European Searchable Tumour Cell and Databank, ESTDAB, as a tool for research in cancer immunology

Identification of immunogenic antigens using a phage-displayed cDNA library from an invasive ductal breast carcinoma tumour.

The identification of immunogenic antigens for serological testing and vaccine development is a major challenge facing cancer immunology research. To study the humoral immune response in patients with breast cancer, a T7 phage display cDNA library from an invasive ductal breast carcinoma was panned on patient serum IgG antibodies. By monitoring the selection with an immunoscreening technique, positive phage-displayed cDNA products reacting with breast cancer patient IgG antibodies were selected. Sequence analysis identified immunogenic antigens such as the cytochrome oxidase I, sp100 and Ran GTPase activating protein. Additionally, immunogenic uncharacterized gene products were also identified. Both the known and unknown immunoselected gene products should offer an additional source for cancer gene discovery for diagnostic testing and vaccine development.

'Essential Components Now in Place' for Clinical Testing of Cancer Vaccine Strategies, Experts Say

ACCORDING to experts at the Cancer Research Institute's "Cancer Vaccines 1994" symposium, held in New York, NY, medicine is entering a "new era of immunologically based treatments for cancer." The conference was the first in a planned series of biennial meetings on cancer vaccines. "We anticipate that this symposium will become the major forum for reporting on vaccine research and will help foster development of the first effective therapeutic cancer vaccine," said Jill O'Donnell-Tormey, PhD, executive director of the New York—based Cancer Research Institute, a nonprofit organization that supports research in cancer immunology. The institute is establishing a cancer vaccine trial registry to serve as a centralized source of information for the scientific and clinical communities about all ongoing vaccine trials. The registry will track progress in the field and maintain status reports on the various trials. Now that researchers are defining the structure of tumor peptides that are recognized

'Essential components now in place' for clinical testing of cancer vaccine strategies, experts say

ACCORDING to experts at the Cancer Research Institute's "Cancer Vaccines 1994" symposium, held in New York, NY, medicine is entering a "new era of immunologically based treatments for cancer." The conference was the first in a planned series of biennial meetings on cancer vaccines. "We anticipate that this symposium will become the major forum for reporting on vaccine research and will help foster development of the first effective therapeutic cancer vaccine," said Jill O'Donnell-Tormey, PhD, executive director of the New York—based Cancer Research Institute, a nonprofit organization that supports research in cancer immunology. The institute is establishing a cancer vaccine trial registry to serve as a centralized source of information for the scientific and clinical communities about all ongoing vaccine trials. The registry will track progress in the field and maintain status reports on the various trials. Now that researchers are defining the structure of tumor peptides that are recognized

Augmentation of lymphokine-activated killer cell cytotoxicity by monoclonal antibodies against human small cell lung carcinoma : Tong AW, Lee JC, Wang R-M, Ordonez G, Stone MJ. Cancer Immunology Research Unit, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246. Cancer Res 1989;49:4103-8

This study examined the lymphokine-activated killer (LAK) cell cytotoxicity on monoclonal antibody (MoAb)-bound tumor cells from the human small cell lung carcinoma cell lines H69 and H128. LAK cells were generated from normal peripheral blood mononuclear cells by incubation with interleukin 2 for 3 or more days. Cells from the LAK culture were cytotoxic to natural killer-sensitive (K562, 84% cytotoxicity) and natural killer-resistant (Daudi, 85%; H69 and H128, 69% and 97%, respectively) cell lines, and to freshly excised human lung (49%) and breast (57%) tumors. LAK cytotoxicity to H69 or H128 cells was significantly augmented by target cell preincubation with the small cell lung carcinoma-reactive MoAbs 1096 (increases of up to 271%) or 5023 (up to 223%). SCLC 5023 or 1096 did not enhance LAK cytotoxicity to Daudi cells of lymphoblastoid origin. Pretreatment of LAK cells with an anti-Fc receptor antibody blocked MoAb augmentation by 1096 or 5023 (but not LAK cytotoxicity), suggesting that LAK-MoAb interaction may be mediated by Fc binding. LAK activity coincided with emergence of a large cell [interleukin 2-stimulated large mononuclear leukocyte (LML)] subset expressing the CD16 and NKH-1 surface determinants. Serial immunophenotyping of the LAK cell culture harvested at Days 3, 5, and 7 indicated that the level of LAK cytotoxicity, with or without MoAb augmentation, correlated with frequency of NKH-1-reactive LMLs. These observations support the hypothesis that LAK cytotoxicity is mediated by a NKH-1-reactive LML subpopulation. Antitumor cytotoxicity may be augmented by tumor-reactive MoAbs through Fc binding to this LML subset.