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We observed lack of clarity and consistency in end point definitions of large randomized clinical trials in diffuse large B-cell lymphoma. These inconsistencies are such that trials might, in fact, address different clinical questions. They complicate interpretation of results, including comparisons across studies. Problems arise from different ways to account for events occurring after randomization including absence of improvement in disease status, treatment discontinuation or the initiation of new therapy. We call for more dialogue between stakeholders to define with clarity the questions of interest and corresponding end points. We illustrate that assessing different end point rules across a range of plausible patient journeys can be a powerful tool to facilitate such a discussion and contribute to better understanding of patient-relevant end points.
What is this article about? This article talks about the lack of clarity and consistency in the definitions of outcomes used in clinical trials that investigate new treatments for diffuse large B-cell lymphoma. This is mainly due to how these different outcome definitions handle events such as absence of improvement in disease status, treatment discontinuation or initiation of new treatment. The authors discuss how these inconsistencies make it hard to interpret the results of individual clinical trials and to compare results across clinical trials.Why is it important? Defining the above events and consequently defining outcomes affects what we can learn from the trials and can lead to different results. Some approaches may not reflect good and bad outcomes for patients appropriately. This makes it challenging for patients, physicians, health authorities and payors to understand the true benefit of treatments under investigation and which one is better.What are the key take-aways? This article serves as a call-to-action for more dialogue among all stakeholders involved in drug development and the decision-making process related to drug evaluations. There is an urgent need for clinical trials to be designed with more clarity and consistency on what is being measured so that relevant questions for patients and prescribing physicians are addressed. Understanding patient journeys will be key to successfully understand what truly matters to patients and how to measure the benefit of new treatments. Such discussions will contribute toward more clarity and consistency in the evaluation of new treatments.
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The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.
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Melanoma , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Italia , Melanoma/patología , Microambiente TumoralRESUMEN
Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies.The virtual Immunotherapy Bridge (December 1st-2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.
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Biomarcadores de Tumor , Melanoma , Biomarcadores de Tumor/metabolismo , Humanos , Factores Inmunológicos , Inmunoterapia , ItaliaRESUMEN
Clinical studies of idiotype (Id) vaccination in patients with lymphoma have established a correlation between the induced anti-Id antibody responses and favorable clinical outcomes. To streamline the production of an Id vaccine, we engineered a small diabody (Db) molecule containing both a B-cell-targeting moiety (anti-CD19) and a lymphoma Id. This molecule (αCD19-Id) was designed to penetrate lymph nodes and bind to noncognate B cells to form an antigen presentation array. Indeed, the αCD19-Id molecule accumulated on B cells in vivo after s.c. administration. These noncognate B cells, decorated with the diabody, could then stimulate the more rare Id-specific B cells. Peptide epitopes present in the diabody linker augmented the response by activating CD4(+) helper T cells. Consequently, the αCD19-Id molecule induced a robust Id-specific antibody response and protected animals from tumor challenge. Such diabodies are produced in a cell-free protein expression system within hours of amplification of the specific Ig genes from the B-cell tumor. This customized product can now be available to vaccinate patients before they receive other, potentially immunosuppressive, therapies.
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Anticuerpos Antiidiotipos/inmunología , Linfocitos B/inmunología , Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Linfoma/inmunología , Linfoma/prevención & control , Transducción de Señal/inmunología , Animales , Antígenos CD19/inmunología , Cartilla de ADN/genética , Ensayo de Inmunoadsorción Enzimática , Escherichia coli , Citometría de Flujo , Ratones , Plásmidos/genéticaRESUMEN
We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.
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Vacunas contra el Cáncer/uso terapéutico , Células de Langerhans/inmunología , Micosis Fungoide/inmunología , Micosis Fungoide/radioterapia , Oligodesoxirribonucleótidos/administración & dosificación , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/inmunología , Adolescente , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Terapia Combinada , Estudios de Factibilidad , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Pronóstico , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Vacunación , Adulto JovenRESUMEN
The classical Hodgkin lymphoma (cHL) environment is comprised of a dense and complex immune cell infiltrate interspersed with rare malignant Hodgkin-Reed-Sternberg (HRS) cells. HRS cells are actively surveilled by endogenous T cells, but data linking phenotypic and functional T-cell states with clonality at the single-cell level in cHL is lacking. To address this knowledge gap, we performed paired single-cell RNA and T-cell receptor sequencing on 14 cHL and 5 reactive lymphoid tissue specimens. Conventional CD4+ T cells dominated the cHL landscape. However, recurrent clonal expansion within effector and exhausted CD8+ T-cell and regulatory T-cell clusters was uniquely observed in cHL specimens. Multiplex flow cytometric analysis revealed that most lymphoma-resident T cells produced effector cytokines upon ex vivo restimulation, arguing against a profound dysfunctional T-cell state in cHL. Our results raise new questions about the nature of T cells that mediate the antilymphoma response following programmed cell death protein 1 (PD-1) blockade therapy in cHL.
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Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/genética , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Citometría de Flujo/métodos , Linfocitos T Reguladores/metabolismo , Análisis de la Célula IndividualRESUMEN
PURPOSE: GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. PATIENTS AND METHODS: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. RESULTS: Thirteen participants enrolled in four dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all four doses with a dose-dependent trend in the durability of the cDC expansion. CONCLUSIONS: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism. See related commentary by Raeder and Drazer, p. 2857.
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Neoplasias , Proteínas Recombinantes de Fusión , Tirosina Quinasa 3 Similar a fms , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Femenino , Persona de Mediana Edad , Anciano , Adulto , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéutico , Dosis Máxima Tolerada , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis. METHODS: An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript. RESULTS: The panel determined unique clinical trial designs tailored to different stages of cancer development-from premalignant to unresectable/metastatic-that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments. CONCLUSIONS: The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most.
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Neoplasias Primarias Secundarias , Neoplasias , Humanos , Neoplasias/terapia , Inmunoterapia/métodos , Sociedades Médicas , Microambiente TumoralRESUMEN
While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR-T), and T cell engagers have improved the response rates in B cell malignancies, the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19 immunotoxin. Single-cell RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (ATAC-Seq) showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B cell acute lymphoblastic leukemia (B-ALL) that relapsed after CD19 CAR-T-targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (BTK) and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.
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Antígenos CD19 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Niño , Humanos , Adulto Joven , Agammaglobulinemia Tirosina Quinasa , Antígenos CD19/genética , Cromatina , Inmunoterapia Adoptiva , Quinasas de Proteína Quinasa Activadas por Mitógenos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genéticaRESUMEN
We designed a whole tumor cell vaccine by "loading" lymphoma tumor cells with CG-enriched oligodeoxynucleotide (CpG), a ligand for the Toll-like receptor 9 (TLR9). CpG-loaded tumor cells were phagocytosed, delivering both tumor antigen(s) and the immunostimulatory CpG molecule to antigen-presenting cells (APCs). These APCs then expressed increased levels of costimulatory molecules and induced T-cell immunity. TLR9 was required in the APCs but not in the CpG-loaded tumor cell. We demonstrate that T cells induced by this vaccine are effective in adoptive cellular therapy for lymphoma. T cells from vaccinated mice transferred into irradiated, syngeneic recipients protected against subsequent lymphoma challenge and, remarkably, led to regression of large and established tumors. This therapeutic effect could be transferred by CD4(+) but not by CD8(+) T cells. A CpG-loaded whole-cell vaccination is practical and has strong potential for translation to the clinical setting. It is currently being tested in a clinical trial of adoptive immunotherapy for mantle-cell lymphoma.
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Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias del Colon/terapia , Islas de CpG/genética , Inmunoterapia Adoptiva , Neoplasias Pulmonares/terapia , Linfoma/terapia , Animales , Células Presentadoras de Antígenos/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Femenino , Citometría de Flujo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Linfoma/genética , Linfoma/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fagocitosis , Linfocitos T Citotóxicos/inmunología , Células Tumorales Cultivadas , VacunaciónRESUMEN
Lymphoma is the fifth most common cancer in the USA. Most lymphomas are classified as non-Hodgkin's lymphoma, and nearly 95% of these cancers are of B-cell origin. B-cell receptor (BCR) surface expression and BCR functional signaling are critical for survival and proliferation of both healthy B cells, as well as most B-lymphoma cells. Agents that inhibit various components of the BCR signaling pathway, as well as parallel signaling pathways, are currently in clinical trials for the treatment of various lymphoma subtypes, including those targeting isoforms of PI3K, mTOR and BTK. In this review, we describe the signaling pathways in healthy mature B cells, the aberrant signaling in lymphomatous B cells and the rationale for clinical trials of agents targeting these pathways as well as the results of clinical trials to date. We propose that the entry into a kinase inhibitor era of lymphoma therapy will be as transformative for our patients as the advent of the antibody or chemotherapy era before it.
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Linfoma/metabolismo , Transducción de Señal , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Linfoma/tratamiento farmacológico , Linfoma/etiología , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
Background: Gray zone lymphoma (GZL) is a rare lymphoma subtype characterized by features intermediate between diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL). The optimal first-line treatment for GZL remains undefined, particularly for patients with poor performance status or baseline organ impairment. Brentuximab vedotin (BV), a targeted therapy that binds to CD30, a TNFR superfamily member involved in NF-kB signaling, has shown promise in the treatment of CD30-positive lymphomas. However, its use in GZL, especially in patients with severe liver impairment, has not been reported previously. Case description: We present a case of a 37-year-old male with GZL and severe liver impairment at initial presentation. The patient initially received monotherapy with BV, which resulted in a marked improvement in liver enzymes and bilirubin levels. Subsequently, combination cytotoxic chemotherapy consisting of dose-adjusted etoposide, prednisone, cyclophosphamide, and doxorubicin (DA-EP_CH) was added. Repeat imaging revealed near complete resolution of lymphadenopathy and significant reduction in hepatosplenomegaly. The patient completed a full course of chemotherapy and achieved a complete response. Follow-up examinations showed no evidence of recurrent disease, and the patient resumed full-time work. Discussion: GZL poses diagnostic challenges due to its overlapping features with DLBCL and cHL. Accurate diagnosis relies on comprehensive histopathological evaluation, immunophenotyping, and molecular analysis. The optimal first-line treatment for GZL remains uncertain. BV shows promise as an addition to chemotherapy in GZL, even in the presence of severe liver impairment. The molecular pathogenesis of GZL is complex and heterogeneous, frequently involving aberrant NF-kB signaling and impaired apoptosis regulation via loss of TP53 expression. Understanding the underlying molecular mechanisms is essential for developing targeted therapies and identifying predictive biomarkers for treatment response. Conclusion: This case demonstrates the successful use of BV as a bridge to cytotoxic chemotherapy in a GZL patient with severe liver impairment, highlighting its potential safety and efficacy even in the setting of end-organ failure. Further investigation is warranted to define optimal treatment strategies, identify predictive biomarkers, and improve outcomes for patients with this rare and challenging lymphoma subtype.
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BACKGROUND: Cancer immunotherapies are generally effective in patients whose tumors contain a priori primed T-cells reactive to tumor antigens (TA). One approach to prime TA-reactive T-cells is to administer immunostimulatory molecules, cells, or pathogens directly to the tumor site, that is, in situ vaccination (ISV). We recently described an ISV using Flt3L to expand and recruit dendritic cells (DC), radiotherapy to load DC with TA, and pattern recognition receptor agonists (PRRa) to activate TA-loaded DC. While ISV trials using synthetic PRRa have yielded systemic tumor regressions, the optimal method to activate DCs is unknown. METHODS: To discover optimal DC activators and increase access to clinical grade reagents, we assessed whether viral or bacterial components found in common pathogen vaccines are an effective source of natural PRRa (naPRRa). Using deep profiling (155-metric) of naPRRa immunomodulatory effects and gene editing of specific PRR, we defined specific signatures and molecular mechanisms by which naPRRa potentiate T-cell priming. RESULTS: We observed that vaccine naPRRa can be even more potent in activating Flt3L-expanded murine and human DCs than synthetic PRRa, promoting cross-priming of TA-reactive T-cells. We developed a mechanistically diverse naPRRa combination (BCG, PedvaxHIB, Rabies) and noted more potent T-cell cross-priming than with any single naPRRa. The naPRRa triplet-as part of Flt3L-primed ISV-induced greater intratumoral CD8 T-cell infiltration, T-cells reactive to a newly defined tumorous neoantigen, durable tumor regressions. CONCLUSIONS: This work provides rationale for the translation of pathogen vaccines as FDA-approved clinical-grade DC activators which could be exploited as immune-stimulants for early phase trials.
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Linfocitos T CD8-positivos , Reactividad Cruzada , Humanos , Animales , Ratones , Vacunación , Edición Génica , InmunizaciónRESUMEN
The multicohort phase 1b KEYNOTE-013 study (NCT01953692) evaluated the safety and efficacy of pembrolizumab in patients with relapsed or refractory NHL who were ineligible for or failed hematopoietic cell transplantation (HCT). Patients received pembrolizumab (cohort 4) or pembrolizumab plus lenalidomide (cohort 5). Primary end points were safety and objective response rate (ORR) per IWG 2007 criteria. Cohort 4 included 89 patients. ORR was 22% (19/86; 90% CI 15-31; 10 CR, nine PR); ORRs by disease type were 48% (10/21), 10% (2/20), 12% (5/41), and 50% (2/4), for PMBCL, FL, DLBCL, and 'other' NHL, respectively. Toxicity was as predicted. Cohort 5 included 19 patients. ORR was 39% (90% CI 20-61; four CR, three PR). Hematologic toxicities were the most common treatment-related AEs. In conclusion, pembrolizumab following HCT ineligibility/failure confirms prior experience in PMBCL but not with NHL subtypes in this study. Additional analyses in DLBCL may not be warranted.
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Anticuerpos Monoclonales Humanizados , Linfoma no Hodgkin , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/tratamiento farmacológico , Lenalidomida/efectos adversos , Recurrencia Local de NeoplasiaRESUMEN
After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
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Vacunas contra el Cáncer , Neoplasias , Células Presentadoras de Antígenos , Vacunas contra el Cáncer/uso terapéutico , Humanos , Factores Inmunológicos , Inmunoterapia/efectos adversos , Neoplasias/prevención & control , Neoplasias/terapiaRESUMEN
Immunotherapies directly enhancing anti-tumor CD8+ T cell responses have yielded measurable but limited success, highlighting the need for alternatives. Anti-tumor T cell responses critically depend on antigen presenting dendritic cells (DC), and enhancing mobilization, antigen loading and activation of these cells represent an attractive possibility to potentiate T cell based therapies. Here we show that expansion of DCs by Flt3L administration impacts in situ vaccination with oncolytic Newcastle Disease Virus (NDV). Mechanistically, NDV activates DCs and sensitizes them to dying tumor cells through upregulation of dead-cell receptors and synergizes with Flt3L to promote anti-tumor CD8+ T cell cross-priming. In vivo, Flt3L-NDV in situ vaccination induces parallel amplification of virus- and tumor-specific T cells, including CD8+ T cells reactive to newly-described neoepitopes, promoting long-term tumor control. Cross-presenting conventional Type 1 DCs are indispensable for the anti-tumor, but not anti-viral, T cell response, and type I IFN-dependent CD4+ Th1 effector cells contribute to optimal anti-tumor immunity. These data demonstrate that mobilizing DCs to increase tumor antigen cross-presentation improves oncolytic virotherapy and that neoepitope-specific T cells can be induced without individualized, ex vivo manufactured vaccines.
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Neoplasias , Viroterapia Oncolítica , Vacunas , Animales , Linfocitos T CD8-positivos , Células Dendríticas , Reactividad Cruzada , Antígenos de Neoplasias , Neoplasias/metabolismo , Vacunas/metabolismoRESUMEN
Ex vivo-expanded tumor-infiltrating lymphocytes infused into lymphodepleted recipients has clear antitumor efficacy. More practical sources of such antitumor lymphocytes would broaden the application of this approach. Previously, we described an in situ vaccination combining chemotherapy with intratumoral injection of CpG-enriched oligonucleotides, which induced T-cell immunity against established lymphoma. An ongoing clinical trial of this maneuver has demonstrated clinical responses in lymphoma patients. Here, we use this vaccine maneuver to generate immune cells for transfer into irradiated, syngeneic recipients. Transferred tumor-specific T-effector (T(eff)) cells preferentially expanded, increasing the T(eff)/T-regulatory (T(reg)) ratio in these "immunotransplantation" recipients and curing large and metastatic tumors. Donor T cells were necessary for tumor protection, and CD8 T-cell immune responses were enhanced by posttransplantation booster vaccination. Hematopoietic stem cell transplantation is a standard therapy for lymphoma. Therefore, in situ tumor vaccination followed by immunotransplantation of harvested tumor-specific T cells could be directly tested in clinical trials to treat otherwise resistant malignancies.
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Vacunas contra el Cáncer/farmacología , Inmunoterapia Adoptiva/métodos , Linfoma de Células B/terapia , Linfocitos T Citotóxicos/trasplante , Linfocitos T Reguladores/citología , Vacunas de ADN/farmacología , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , ADN/inmunología , ADN/farmacología , Inmunización Secundaria , Inyecciones Intralesiones , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Oligodesoxirribonucleótidos , Índice de Severidad de la Enfermedad , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Follicular lymphoma is an indolent lymphoma associated with a relapsing course. Immunization with tumor B cell idiotype (Id; a unique variable region of surface B cell immunoglobulin) may induce humoral and cellular immune response against the tumor. Based on promising results from early phase clinical trials with Id vaccine, three Phase III trials were initiated, which, despite failing to meet their primary end points, still provided a glimmer of optimism. This article describes the clinical development of the Id vaccine against follicular lymphoma, outlines the outcomes of clinical trials and delineates the future prospects for the integration of the idiotype vaccine into follicular lymphoma treatment.
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Vacunas contra el Cáncer/uso terapéutico , Idiotipos de Inmunoglobulinas/inmunología , Inmunoterapia , Linfoma Folicular/terapia , Vacunas contra el Cáncer/inmunología , Ensayos Clínicos como Asunto , Medicina de PrecisiónRESUMEN
We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; pâ¯=â¯0.065; complete response 37.5% vs. 0%; pâ¯=â¯0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; pâ¯=â¯0.055), KLHL14 (30.0% vs. 0%; pâ¯=â¯0.046), and LRP1B (30.0% vs. 6.2%; pâ¯=â¯0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; pâ¯=â¯0.047) and ROS1 (0% vs. 50.0%; pâ¯=â¯0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.