Immune Responses In Cancer Patients Research Articles

Impaired and imbalanced cellular immunological status assessed in advanced cancer patients and restoration of the T cell immune status by adoptive T-cell immunotherapy

Recent progress has been made in understanding the mechanisms of antitumor immune responses, which may further clarify the immune status of cancer patients. In this study, we performed a detailed evaluation of the immunological status of 47 patients with advanced solid cancer, who had received no immunosuppressive treatment, and compared the results with 32 healthy subjects. Flow-cytometry data for peripheral blood were obtained using 19 monoclonal antibodies against various cell surface and intracellular molecules. Absolute numbers of T cells, several T cell subsets, B cells, and NK cells were significantly decreased in patients compared with healthy subjects. The percentage of CD27(+)CD45RA(+) T cells was lower and that of CD27(-)CD45RA(-) T cells was higher in patients compared with controls. Regulatory and type 2 helper T cells were elevated in patients relative to healthy subjects. The percentage of perforin(+) NK cells was significantly lower in patients than in controls. These results suggest a dysfunctional anti-tumor immune response in cancer patients. Furthermore, peripheral blood from 26 of 47 cancer patients was analyzed after adoptive T cell immunotherapy (ATI). ATI increased the number of T cell subsets, but not B and NK cells. The number and percentage of regulatory T cells decreased significantly. These results suggest that ATI can restore impaired and imbalanced T cell immune status.

The association between CD4+ CD25+ regulatory T cells and non-small cell lung carcinoma

Lung cancer is the second most common malignancy in the USA, and it is the leading cause of cancer-related deaths among men and women. Regulatory T cells (Tregs) in peripheral blood play crucial roles in suppressing antitumor immune responses in cancer patients. A defect in the immune response may contribute to tumor growth. This study was conducted to test the hypothesis that regulatory T cell lymphocytes might contribute to immune dysfunction in non-small cell lung carcinoma (NSCLC) patients, with a specific aim of determining its role in the development and progression of NSCLC. CD4+ CD25+ Treg cell enumeration by flow cytometry was performed for 30 NSCLC patients both preoperatively and postoperatively, together with 20 controls. Higher percentages of CD4+ CD25+ Treg cells were found in NSCLC patients both pre- (11.24 ± 5.34) and postoperatively (8.75 ± 4.66) in comparison to the control group (2.16 ± 0.97); this difference was statistically significant (p < 0.001). From this study we concluded that the CD4+ CD25+ Treg population increased significantly and correlated with clinical staging in NSCLC patients: healthy donor < stage I < stage II < stage III whether preoperatively (r = 0.5, p = 0.005) or postoperatively (r = 0.4, p = 0.008). Treg cells decreased significantly after surgical removal of the tumors, from 11.24 ± 5.34 to 8.75 ± 4.66; the difference was statistically significant (p < 0.001). From this study we concluded that CD4+ CD25+ Treg lymphocytes increased in NSCLC patients; their percentage correlates with tumor staging, and it decreases following surgical removal of the tumor. Thus, manipulation of these regulatory T cells could lead to new strategies for the treatment of cancer.

Development of a biosensor-based immunogenicity assay capable of blocking soluble drug target interference

As with other protein therapeutics, trebananib (AMG 386), an investigational peptide Fc-fusion protein (“peptibody”) that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) with the Tie2 receptor, has the potential to trigger an immune response in cancer patients treated with the therapeutic. An electrochemiluminescence bridging anti-drug antibody (ADA) assay that was utilized to support early-phase clinical trials in the development of trebananib was found to lack adequate sensitivity and drug tolerance in later-phase clinical studies when higher doses of trebananib were administered. Therefore, we developed a surface plasmon resonance (SPR) immunoassay method utilizing a secondary confirmatory detector antibody (goat anti-human IgG F[ab′]2) known to cross-react with human IgG and IgM to better assess the potential impact of immunogenicity on the pharmacokinetics, pharmacodynamics, and toxicity of trebananib. The SPR method was more sensitive than the electrochemiluminescence bridging assay because of signal amplification from the confirmatory binding of the detector antibody; drug tolerance was improved since antibody binding avidity does not affect detection on this platform. Despite the inability of the confirmatory detector antibody to bind angiopoietins in protein-free buffer, false-positive ADA results were generated from patient serum samples containing Ang1 and Ang2 through an apparently specific binding between the angiopoietins and the confirmatory detector antibody, likely mediated by the interaction of the angiopoietins with serum immunoglobulins. Addition to the sample diluent of a human antibody that specifically binds to Ang1 and Ang2 with high affinity resulted in a complete block of angiopoietin interference without affecting ADA detection. This biosensor-based assay provides a reliable method for assessing immunogenicity in phase 3 clinical trials.

Developing an effective breast cancer vaccine: Challenges to achieving sterile immunity versus resetting equilibrium

IntroductionEvading immune destruction is an emerging hallmark of cancer. Immunotherapy of cancer is categorized as either specific stimulation of the immune system by active immunization, with cancer vaccines, or passive transfer of humor or cellular materials, such as, tumor specific antibodies (including immunomodulators) or adoptive cell therapy that inhibit the function of- or directly kill tumor cells. Modulation of immune response in cancer patients is the result of a balanced activity of T regulators and T effector cells. Methods and resultsWe will present the current information and the prospects for the future of immunotherapy in patients with breast cancer including tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy. DiscussionActive immunotherapy in breast cancer and its implementation into clinical trials has largely been a frustrating experience in the last decades. After many years of controversy, the concept that the immune system regulates cancer development is experiencing a new resurgence. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. It has been also clear that the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. ConclusionWhat do we know about tumor immunogenicity and how might we therapeutically improve tumor immunogenicity? The first vaccine and the first immunomodulating agent were recently approved by the US Food and Drug Administration (FDA) for the treatment of prostate cancer (sipuleucel-T) and melanoma (ipilimumab), respectively. The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signalingsignaling pathways that regulate immune responses in the tumor microenvironment.

Immune Response after a Single Dose of the 2010/11 Trivalent, Seasonal Influenza Vaccine in HIV-1–Infected Patients and Healthy Controls

Background: Immune response rates following influenza vaccination are often lower in HIV-infected individuals. Low vitamin D levels were correlated with weak immune response in cancer patients and are known to be lower in HIV-infected patients. Methods: Diagnostic study to determine immune response against the H1N1v component after a single, intramuscular dose of the 2010/11 seasonal, trivalent influenza vaccine (TIV) in adult HIV-infected and healthy controls scheduled for influenza vaccination (ClinicalTrials.gov Identifier: NCT01017172). Influenza A/H1N1 antibody titers (AB) were determined before and 21 days after vaccination by hemagglutination inhibition assay. Results: Immune response was not different between HIV-infected patients (n = 36) and healthy controls (n = 42) who were previously naïve to the H1N1v component of the TIV. Comparing HIV-infected patients (n = 55) and healthy controls (n = 63) who had received 1 or 2 doses of an AS03 adjuvanted H1N1 vaccine in the previous winter season (2009/10), seroconversion rate and the geometric mean AB titer after TIV of the HIV-infected patients were more than twice as high compared to healthy controls. This difference was mainly driven by the 2-dose schedule for HIV patients in 2009/10. Vitamin D levels were lower in HIV patients but did not correlate with immune response. Conclusion: HIV-infected patients who had received 1 or 2 doses of an adjuvanted H1N1 vaccine in the previous year (2009/10) had a significant higher seroconversion rate following TIV as compared to healthy controls, indicating a stronger memory cell response due to the 2-dose schedule.

Plasma endothelial protein C receptor influences innate immune response in ovarian cancer by decreasing the population of natural killer and TH17 helper cells

In spite of the growing importance of endothelial protein C receptor/active protein C (EPCR/aPC) in tumor biology, their impact on immunological homeostasis remains largely unexplored. The objective of this study was to assess whether soluble plasma endothelial protein C receptor (sEPCR), which is a regulator of circulating aPC, is involved in innate immune response in cancer patients. In the Ovcar-3 ovarian cancer line, the role of aPC in secretion of cytokines was analyzed. In parallel, in 33 patients, with a diagnosis of ovarian epithelial cancer, sEPCR was quantified, blood immune cell phenotypes were determined by flow cytometry and plasma cytokines were evaluated using a protein array. Spearman's rank correlation coefficients (r) and coefficient significance was determined by a statistical hypothesis test (α=0.05). Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100 ± 28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥ 0.60); and iv) high levels of sEPCR correlate with high levels of plasma bioactive proteins such as insulin-like growth factor-2 (IGFII), IL-13rα, macrophage inflammatory protein (MIP1α) and matrix metalloproteinase-7 (MMP-7) that have already been proposed as biomarkers for ovarian cancer and particularly those with poor prognosis. In conclusion, sEPCR produced by ovarian cancer cells, by modulating circulating aPC, influences the secretory behavior of tumor cells (cytokines and interleukins). Consequently, sEPCR in turn acts on the innate immune response by decreasing effector cells such as natural killer and T helper cells (TH2, TH17 and TH21).

Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients

Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.

Three are better than one: plasminogen receptors as cancer theranostic targets

Activation of plasminogen on the cell surface initiates a cascade of protease activity with important implications for several physiological and pathological events. In particular, components of the plasminogen system participate in tumor growth, invasion and metastasis. Plasminogen receptors are in fact expressed on the cell surface of most tumors, and their expression frequently correlates with cancer diagnosis, survival and prognosis. Notably, they can trigger multiple specific immune responses in cancer patients, highlighting their role as tumor-associated antigens. In this review, three of the most characterized plasminogen receptors involved in tumorigenesis, namely Annexin 2 (ANX2), Cytokeratin 8 (CK8) and alpha-Enolase (ENOA), are analyzed to ascertain an overall view of their role in the most common cancers. This analysis emphasizes the possibility of delineating new personalized therapeutic strategies to counteract tumor growth and metastasis by targeting plasminogen receptors, as well as their potential application as cancer predictors.

Abstract 4379: Framing therapeutic opportunities in tumor-activated gametogenic programs.

Abstract Tumors frequently activate genes whose expression is otherwise restricted to testes, and which can invoke a humoral immune response in cancer patients. Given their germline-biased expression pattern, these Cancer-Testes antigens (CT-antigens, CTAs) may afford the potential for an extraordinary therapeutic window, if they are required for tumorigenic behaviors. While the function of CTAs in normal and neoplastic settings remains obscure, mounting evidence suggests that specific CTAs can contribute to tumor cell autonomous behaviors. To generate a more comprehensive understanding of the functional roles of CTAs, we have employed an unbiased, multi-dimensional, loss of function discovery platform to systematically assess the contribution of CT-antigens to a range of tumorigenic signaling pathways and phenotypes. By employing a diverse panel of 11 tumor-derived cell lines to screen 120 CTAs, we find that these tumor-activated genes are required to support a number of the hallmarks of cancer. For example, we reveal multiple MAGE family members that mitigate response to mitotic stress and hypoxia. Additionally, we find that the SPANX family of CTAs contributes to β-catenin signaling. Finally, we reveal a role for GAGE proteins in supporting the viability of a range of tumor types. The diversity of neoplastic settings analyzed in our primary screen allowed for the identification of CTAs that support tumor cell fitness in multiple disease backgrounds. For example, we have uncovered CTAs that contribute to mitochondrial integrity in lung, breast, melanoma and sarcoma. Alternatively, we find that CTAs can display lineage selective dependencies, such as supporting TGFβ signaling in claudin-low breast tumors. Taken together, these observations support the hypothesis that CTAs are frequently integrated into the tumor cell regulatory environment to support cell division, survival and modulate stress responses by regulating key signaling pathways. Thus, CT-antigens present previously unrecognized tumor-specific vulnerabilities that may be exploited for therapeutic intervention. Citation Format: Kathleen Corcoran, Patrick Taus, Rebecca Sinnott, Kimberly Maxfield, Joshua Wooten, Angelique Whitehurst. Framing therapeutic opportunities in tumor-activated gametogenic programs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4379. doi:10.1158/1538-7445.AM2013-4379

Vemurafenib reverses immunosuppression by myeloid derived suppressor cells

Myeloid derived suppressor cells (MDSCs) suppress innate and adaptive immunity, thereby limiting anti-tumor immune responses in cancer patients. In patients with advanced melanoma, the phenotype and function of MDSCs remains controversial. In our study, we further explored two distinct subpopulations of MDSCs and investigated the impact of Vemurafenib on these cells. Flow cytometry analysis revealed that in comparison to healthy donors and patients with localized disease, PBMCs from patients with metastatic melanoma showed an increased frequency of CD14(+) HLA-DR(-/low) monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14(-) CD66b(+) Arginase1(+) granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T-cell proliferation, which was tested in CFSE-based proliferation assays. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. According to our in vivo finding, conditioned medium (CM) from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro than CM from untreated melanoma cells. In conclusion, patients with advanced melanoma show increased levels of moMDSCs, and of a population of CD14(-) CD66b(+) Arginase1(+) grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T-cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as part of future immunotherapies.

Characterization of Ewing sarcoma associated cancer/testis antigens

The prognosis of patients suffering from tumors of the Ewing family (EFT) is still poor. Immunotherapy strategies are pursued and EFT-specific antigens have to be identified as targets for cytotoxic T-lymphocytes (CTL). Due to the lack of expression of cancer/testis antigens (CTA) in normal tissues, these antigens are partially able to induce immune responses in cancer patients. Therefore, they are promising targets for immunotherapy. EFT are characterized by chromosomal rearrangements involving members of the TET (translocated in liposarcoma, Ewing sarcoma breakpoint region 1, TATA box binding protein-associated factor 15) family of RNA binding proteins and members of the E-26 (ETS) family of transcription factors. The resulting onco-fusion proteins are highly specific for EFT and downstream targets of TET-ETS represent candidate tumor specific antigens. In order to identify new EFT-associated CTA, we analyzed microarray-data sets from EFT and normal tissues from the Gene Expression Omnibus (GEO) database. The impact of TET-ETS on expression of CTA was analyzed using GEO data sets from transgenic mesenchymal stem cells. One CTA with high specificity for EFT is lipase I (LIPI, membrane-associated phospholipase A1-β). CTL specific for LIPI-derived peptides LDYTDAKFV and NLLKHGASL were able to lyse HLA-A2 positive EFT cells in vitro which confirms the possible role of LIPI and other CTA for EFT-immunotherapy.

Therapeutic Dendritic Cell-Based Cancer Vaccines: The State of the Art

Dendritic cells (DCs) are the most potent professional antigen-presenting cells, capable of initiating proper adaptive immune responses. Although tumor-infiltrating DCs are able to recognize cancer cells and uptake tumor antigens, they often have impaired functions because of the immunosuppressive tumor milieu. Therefore, DCs are targeted by therapeutic means either in vivo or ex vivo to facilitate tumor antigen presentation to T cells and induce or promote efficient antitumor immune responses in cancer patients. This immunotherapeutical approach is defined as specific active tumor immunotherapy or therapeutic cancer vaccination. In this review we briefly discuss general aspects of DC biology, followed by a thorough description of the current knowledge and optimization trends of DC vaccine production ex vivo, including various approaches for the induction of proper DC maturation and efficient loading with tumor antigens. We also discuss critical clinical aspects of DC vaccine application in cancer patients, including protocols of administration (routes and regimens), individualization of tumor immunotherapy, prediction and proper evaluation of immune and clinical responses to immunotherapy, and the critical role of combining tumor immunotherapy with other cancer treatment strategies to achieve maximal therapeutic effects.

Perioperative Clinical Interventions That Modify the Immune Response in Cancer Patients

The immune system plays a pivotal role against cancer. The development of a successful immune response involves the balance between the Th1 (antitumor) and Th2 (protumor) responses. Once this balance is lost, diseases such as cancer may become apparent. Surgical stress, volatile anaesthetics, opioids and blood transfusions are known to favour a Th2 response that manifests as immune suppression. During surgery the load of circulating malignant cancer cells is increased by tumour manipulation. These cancer cells can migrate and seed in distant tissues and form metastasis. Also, some cancer patients may present with micrometastasis that may become invasive if left untreated. Therefore, the perioperative period is a moment of immunological vulnerability in cancer patients. A better understanding of the factors that affect the Th1/Th2 balance may allow anaesthesiologists to identify patients at high risk for cancer recurrence. This review describes the perioperative interventions that can alter the Th1/Th2 balance, during the perioperative period of oncological surgery.

Circulating regulatory T cells of cancer patients receiving radiochemotherapy may be useful to individualize cancer treatment

Background and purposeDendritic cells (DCs) and regulatory T cells (Treg) play a major role in anti-tumor immune response of cancer patients. We investigated the effect of radiochemotherapy on patients’ blood immune cells and their predictive value for tumor response. Materials and methodsDCs and Treg of colorectal cancer (CRC) or breast cancer (BC) patients were examined through multicolor flow cytometry before the beginning and after the first week of radiochemotherapy (RCT). DCs were stained for BDCA1 and BDCA2, Treg were stained for CD4, CD25, CD127 and FoxP3. IL-2, IL-10 and TNF-α plasma levels of CRC patients were also determined. We examined the interrelationship between immune cell count alterations, applied dose values, cytokine plasma levels as well as histopathological parameters. ResultsDCs were increased in BC and CRC patients compared to healthy control individuals (HC). CRC patients had higher levels of Treg (59.0%) compared to BC patients (31.3%) and HC (27.0%). Treg of CRC (58.7% vs. 41.3% p<0.001) but not BC patients (31.3% vs. 38.8%, p=0.164) decreased distinctly after the first week of radiation therapy. Applied dose values and decrease of Treg correlated positively (r=0.216, p=0.054). We also found a positive correlation of IL-10 plasma levels and Treg levels (r=0.748, p=0.021). CRC patients with favorable tumor stage (<ypT3a) have higher levels of Treg after 5days of RCT (49.4% vs. 34.0%, p=0.043). ConclusionHigher Treg levels are associated with favorable tumor stage. We hypothesize that a dramatic decrease of Treg after in vivo irradiation may be a good indicator for necessary dose adjustments in radiation therapy of CRC patients.

INF-γ production of NK cells is suppressed in cancer patients. (45.10)

Abstract Natural killer (NK) cells are the innate immune system that play an important role in killing viral infected and transformed cancer cells by direct cell to cell interaction. NK cells also secrete cytokines such as interferon (IFN)-γ and TNF-α which primes subsequent adaptive immune responses. However, tumor cells employ many different strategies to evade NK cells. Moreover, tumor cells secrete molecules to directly inhibit the function of immune cells of both innate and adaptive immunity. Here, we designed to investigate whether NK cells from cancer patients exhibit an altered ability to produce INF-γ. The results showed that peripheral blood mononuclear cells (PBMC) and purified NK cells of the cancer patients had suppressed ability to produce IFN-γ. Therefore, we propose that impaired IFN-γ production in peripheral blood mononuclear cells and in purified NK cells reflects immunosuppression and inadequate antitumor immune response in cancer patients. Thus, the measurement of INF-γ producing ability of NK cells in clinical blood samples may allow to assess the impact of immunosuppression on these effector cells, and this information may be helpful in understanding cancer and pathogenesis.

Abstract SY24-02: Imaging immune responses in cancer patients

Abstract Antigen-specific immunotherapy has recently progressed through the development of effective therapeutic vaccinations in advanced melanoma (1,2) and prostate cancer (3). Antigen-specific immune responses in cancer patients can also be induced by exploiting autologous dendritic cells (DCs) that are “educated” ex vivo; i.e., DCs that are appropriately activated and loaded with tumor antigens. DCs are the most potent antigen-presenting cells of the immune system and play a central role in the induction and maintenance of antigen-specific immunity (4). These cells capture and process antigen and migrate to the lymph nodes (LNs), where they present the antigen to the adaptive arm of the immune system, inducing antigen-specific T- and B-cell responses. The detection of vaccine-induced immune responses in vivo using a clinically applicable means is critical for the optimization of novel immunotherapies. Positron emission tomography (PET) is a widely available, highly sensitive imaging modality for the in vivo visualization and quantification of molecular processes at a cellular level. Furthermore, whole body imaging allows localization in a longitudinal fashion. These features are necessary to measure immune responses by quantification of the low numbers of proliferating T and B cells early after vaccination in relevant LNs. Thus far, investigators have mainly exploited [18F]-labeled fluoro-2-deoxy-2-d-glucose ([18F]FDG) for PET imaging of proliferating cells, based on the increased glucose metabolism of these cells. Recently, novel tracers have been developed that facilitate imaging of other cellular processes: [18F]-labeled 3α-fluoro-3α-deoxy-thymidine ([18F]FLT) was designed as a tracer for cell proliferation (5) and is increasingly being applied in oncology. However, it has been recognized that enhanced nucleoside demand is not restricted to tumor cells (6). A successful vaccination results in the proliferation of activated lymphocytes in a highly controlled manner within LNs. This proliferation is accompanied by a large metabolic switch in lymphocytes and could serve as a marker of immune responsiveness. We demonstrate that [18F]FLT PET can be used to directly monitor antigen-specific immune responses in vivo shortly after therapeutic vaccination, because it offers a sensitive tool to study the kinetics and localization of induction of antigen-specific lymphocyte activation upon vaccination with antigen-loaded autologous DCs (7). Melanoma patients with lymph node (LN) metastases received DC vaccine therapy, injected intranodally, followed by [18F]FLT PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 weeks. This selective [18F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 × 105 DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4+ and CD8+ T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [18F]FDG. Therefore, [18F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. Recently published large phase III trials, demonstrate that immunotherapies can be effective even in advanced cancer patients. Both antigen-specific (2,3) and nonantigen specific agents (2) have been approved by the Food and Drug Administration. Considering the amount of effort poured into the development of these novel agents, PET-based monitoring will advance our knowledge of the immunological processes that precede the failure or success of novel immunotherapies. Furthermore, it should vastly improve efficient application by aiding in individualized decision making.

A Mathematical Model of the Enhancement of Tumor Vaccine Efficacy by Immunotherapy

TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy.

Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study

Influenza vaccination is recommended to cancer patients undergoing chemotherapy, but vaccine coverage remains low. During the 2009 influenza pandemic, French recommendations were to vaccinate immunocompromised patients with two doses of adjuvanted vaccine. This study aimed to evaluate vaccine immunogenicity in cancer patients receiving chemotherapy. VACANCE is a prospective open-label study that evaluated the immunogenicity and safety of two doses of AS03A-adjuvanted H1N1v vaccine in cancer patients receiving cytotoxic and/or targeted therapies. Serum haemagglutination-inhibited antibody titres against influenza A H1N1v were measured at days 1, 21, and 42, to estimate the proportion of participants with antibody titres ≥ 1 : 40 [seroprotection rate (SPR)], the efficacy of seroconversion, and factors that increased the geometric mean titre. Sixty-five patients were included. At baseline, 5% of patients had vaccine strain titres of specific haemagglutination inhibition antibodies that were ≥ 1 : 40. After one and two doses of vaccine, SPRs were 48% and 73%, respectively, and seroconversion rates were 44% and 73%, respectively. Vaccine-related adverse events were mild to moderate. A single dose of AS03-adjuvanted A/H1N1 vaccine triggered a low immune response in cancer patients on chemotherapy depending on their treatment type and frequency. Two doses are needed for these cancer patients.

Towards Curative Cancer Immunotherapy: Overcoming Posttherapy Tumor Escape

The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.

Immunogenicity of an Inactivated Monovalent 2009 Influenza A (H1N1) Vaccine in Patients Who Have Cancer

The immune response of patients who have cancer, who may be receiving immunosuppressive therapy, is generally considered to be decreased. This study aimed to evaluate the immune response of cancer patients to the 2009 influenza A (H1N1) vaccine. We conducted a prospective single site study comparing the immune response after H1N1 vaccination of healthy controls (group A), patients who had solid tumors and were taking myelosuppressive chemotherapy (group B), patients who had solid tumors and were taking nonmyelosuppressive or no treatment (group C), and patients who had hematologic malignancies (group D). At 2-6 weeks after vaccination, seroconversion was observed in 80.0% of group A (95% confidence interval [CI], 65.0%-89.7%), 72.2% of group B (95% CI, 55.9%-84.3%), 87.0% of group C (95% CI, 72.2%-94.7%), and 75.0% of group D (95% CI, 52.8%-89.2%) (p = NS). The geometric mean titer ratio, that is, geometric mean factor increase in antibody titer after vaccination, was 12.6 (95% CI, 7.9-19.9), 12.7 (95% CI, 7.3-22.1), 23.0 (95% CI, 13.9-38.2), and 12.1 (95% CI, 5.3-27.9) (p = NS), and the seroprotection rates were 95.5% (95% CI, 84.0%-99.6%), 79.0% (95% CI, 63.4%-89.2%), 90.5% (95% CI, 77.4%-96.8%), and 90.0% (95% CI, 71%-98.7%) in the corresponding groups (p = NS). Immune responses were robust regardless of malignancy, or time intervals between the use of myelosuppressive or immunosuppressive medications and vaccination. No participants developed clinical H1N1 infection. Cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls.