Response In Advanced Cancer Patients Research Articles

Effect of Concomitant Use of Proton Pump Inhibitors on Immunotherapy Clinical Response in Advanced Cancer Patients: Real-Life Setting.

The alteration of the gut microbiota mediated by proton pump inhibitor (PPI) drugs could be involved in the clinical response associated with immunotherapy [immunocheckpoint inhibitors (ICIs)] in cancer patients. Due to the current controversy in the scientific evidence, it has been proposed to evaluate the correlation between the concomitant use of PPIs and the effectiveness of immunotherapy in a real clinical practice setting. Single-center retrospective cohort study that included patients treated with anti-PD-1 or anti-CTLA4, including nivolumab, pembrolizumab, atezolizumab, or the combination ipilimumab-nivolumab in metastatic neoplastic disease. The clinical effectiveness of ICI, measured in progression-free survival (PFS) and overall survival (OS), was compared between the PPI-use versus PPI-no-use group. PPI-use group was associated with lower PFS [hazard ratio (HR):1.89 (1.38-2.59), P<0.001] and OS [HR: 2.02 (1.45-2.82), P<0.001] versus PPI-no-use group. However, this difference was not observed for pembrolizumab PFS [HR: 1.38 (0.93-2.39), P=0.160] and OS [HR: 1.41 (0.81-2.44), P=0.187]. The study showed significantly lower PFS and OS in the chronic PPI-use group (P<0.001), recent PPI-use group (P<0.001) and concomitant PPI-use group (P=0.001, 0.007) versus PPI-no-use group. However, late PPI use >30 days after the onset of ICI has no significant effect on the efficacy of treatment [HR: 0.92 (0.49-1.70), P=0.791; HR: 1.10 (0.59-2.05), P=0.756]. The concomitant use of PPIs in immunotherapy is associated with worse clinical outcomes compared with the group without PPI use. In addition, the study shows how the late use of PPIs does not have a significant effect on clinical benefit.

Abstract P049: A simplified, potentially point-of-care (POC), electrode method detects changes in the amount of cfDNA/ctDNA and evaluates the response of advanced cancer patients to therapy

Abstract Rapid assessment of therapy for advanced cancer, especially immunotherapy (IO), is critical. For advanced cancers most therapies, even targeted/personalized ones fail. Even worse, IO has been reported to cause more than doubling in the cancer growth rate (defined as hyper-progressive disease or HPD) in 5-40% (typically ~20%) of patients. Early identification of HPD, or any inactive therapy, and switching to an effective therapy can be lifesaving. Though a consensus has not emerged, there are several reports that describe sensitization to chemotherapy following failed immunotherapy, this suggests that, at least in some cases, switching results in dramatic benefit. Due to inflammatory infiltrates causing “pseudoprogression” (false readings of cancer progression) early during treatment with IO, ineffective IO is often continued for 4-6 months before imaging can definitively say the IO is failing. During this time progressive, potentially fatal cancer growth, as well as medical and financial side effects can occur. The cost of this ineffective or counterproductive IO is typically $10,000 to over $20,000 a month. There are numerous reports of highly sensitive mutation based, or methylation sequence based, cfDNA signatures and methods. Unfortunately, they are inherently difficult tests which typically cost thousands of dollars and do not report the results to clinicians for 1 to 2 weeks. They have not been adopted for routine use to monitor on every visit basis and allow near real-time adjustment of therapy. Rapid detection of failure can lead to lifesaving therapy changes; detection of benefit can enhance compliance and improve clinical outcomes. Previously a research lab style solid gold electrode, requiring artful polishing and reuse, has been reported to be selectively sensitive to cancer DNA due to ctDNA’s altered pattern of methylation. Electrochemical detection of the binding of cfDNA, following a 10-minute incubation, has been published. Details of the dramatically revised and optimized binding methodology are in the methods section of this poster. Compared to previous methods an over 2-fold increase in cfDNA binding is shown. Cancer samples not distinguishable from normal with the previous method show statistically significant detection with the new method. Dramatically increased ability to separate cancer from normal DNA is shown. The new method uses inexpensive, clinically and POC suitable, disposable electrodes; it is highly sensitive to clinical samples. 5 µL of a 10 pg/ul sample provides reproducible readings. cfDNA from normal persons generates readings significantly different than from those with cancer (p &amp;lt; .01). Patient time courses illustrate the correlation of the electrode response with cancer burden and suggests this is a monitoring tool that should be compared to, and may have benefits over, previously approved monitoring tests for advanced cancer such as carcinoembryonic antigen (CEA). Citation Format: Floyd Taub, Matt Russo, Shannon Tunney, Suzin Wright, Chuck Henry. A simplified, potentially point-of-care (POC), electrode method detects changes in the amount of cfDNA/ctDNA and evaluates the response of advanced cancer patients to therapy. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P049.

Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

BackgroundRecent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct.MethodsWe studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5).ResultsTreatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05).ConclusionAC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

Revisiting the association between skin toxicity and better response in advanced cancer patients treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibition (ICI) improves survival outcomes for patients with several types of cancer including metastatic melanoma (MM), but serious immune-related adverse events requiring intervention with immunosuppressive medications occur in a subset of patients. Skin toxicity (ST) has been reported to be associated with better response to ICI. However, understudied factors, such as ST severity and potential survivor bias, may influence the strength of these observed associations.MethodsTo examine the potential confounding impact of such variables, we analyzed advanced cancer patients enrolled prospectively in a clinicopathological database with protocol-driven follow up and treated with ICI. We tested the associations between developing ST, stratified as no (n = 617), mild (n = 191), and severe (n = 63), and progression-free survival (PFS) and overall survival (OS) in univariable and multivariable analyses. We defined severe ST as a skin event that required treatment with systemic corticosteroids. To account for the possibility of longer survival associating with adverse events instead of the reverse, we treated ST as a time-dependent covariate in an adjusted model.ResultsBoth mild and severe ST were significantly associated with improved PFS and OS (all P < 0.001). However, when adjusting for the time from treatment initiation to time of skin event, severe ST was not associated with PFS benefit both in univariable and multivariable analyses (P = 0.729 and P = 0.711, respectively). Receiving systemic steroids for ST did not lead to significant differences in PFS or OS compared to patients who did not receive systemic steroids.ConclusionsOur data reveal the influence of time to event and its severity as covariates in analyzing the relationship between ST and ICI outcomes. These differences in outcomes cannot be solely explained by the use of immunosuppressive medications, and thus highlight the importance of host- and disease-intrinsic factors in determining ICI response and toxicity.Trial registration: The patient data used in this manuscript come from patients who were prospectively enrolled in two institutional review board-approved databases at NYU Langone Health (institutional review board #10362 and #S16-00122).

Association between alcoholism and symptom expression, patient symptom goals, and clinical response in advanced cancer patients.

The aim of this study was to determine the influence of alcoholism on symptom expression, personalized symptom goal (PSG) and patient goal response (PGR), and patient global impression (PGI) in advanced cancer patients. This was a secondary analysis of an international multicenter study. Advanced cancer patients who had a history of alcohol dependence positive, according to CAGE (cut down, annoy, guilt, eye-opener), were selected. Thirty patients (3.45%) were CAGE-positive. This sample was matched with 30 patients with similar characteristics who were CAGE-negative. Patients rated symptom intensity by using the Edmonton Symptom Assessment Score (ESAS) at admission (T0) and then after 1 week. For each symptom, patients reported their PSG. After a week of comprehensive palliative care, PSG was measured again (T7), as well as the achievement of PGR, and PGI. Minimal clinically important difference (MCID) was calculated by PGI of improvement or deterioration at T7 (bit better or a little worse, respectively). A significant decrease in intensity was found for most symptoms in both groups. In CAGE-negative and CAGE-positive patients, most patients had a PSG of ≤ 3 for all ESAS items as a target at T0. All PSG targets did not changed significantly after 1 week of palliative care in both groups. Although CAGE-positive basically had unfavorable PGI and PGR, a statistical significance was achieved only for appetite (P = 0.037; ANOVA test). In CAGE-negative patients, Karnofsky was the only factor independently associated with PGI for pain and dyspnea. Factors independently associated with PGI for nausea were symptom intensity at T0 and home situation. In CAGE-positive patients, Karnofsky was independently associated with PGI for pain, nausea, and well-being. Symptom intensity at T0 was independently associated with PGI for weakness. CAGE-positive advanced cancer patients favorably responded to a palliative care intervention. No greater differences have been found in comparison with CAGE-negative patients for PSG, PGR, and PGI, except for appetite. Further studies with large number of patients could confirm some trends observed in this study.

Differential localization of PD-L1 and Akt-1 involvement in radioresistant and radiosensitive cell lines of head and neck squamous cell carcinoma.

Immunotherapy by blockade of the PD-1/PD-L1 checkpoint demonstrated amazing tumor response in advanced cancer patients including head and neck squamous cell carcinoma (HNSCC). However, the majority of HNSCC patients still show little improvement or even hyperprogression. Irradiation is currently investigated as synergistic treatment modality to immunotherapy as it increases the number of T-cells thereby enhancing efficacy of immunotherapy. Apart from this immunogenic context a growing amount of data indicates that PD-L1 also plays an intrinsic role in cancer cells by regulating different cellular functions like cell proliferation or migration. Here, we demonstrate opposing membrane localization of PD-L1 in vital and apoptotic cell populations of radioresistant (RR) and radiosensitive (RS) HNSCC cell lines up to 72 h after irradiation using flow cytometry. Moreover, strong PD-L1 expression was found in nuclear and cytoplasmic cell fractions of RR. After irradiation PD-L1 decreased in nuclear fractions and increased in cytoplasmic fractions of RR cells. In contrast, RS cell lines did not express PD-L1, neither in the nucleus nor in cytoplasmic fractions. Additionally, overexpression of PD-L1 in RS cells led to a proportional increase of vital PD-L1 positive cells after irradiation. Moreover, co-immunoprecipitation experiments revealed an interaction between Akt-1 and PD-L1, mostly in irradiated RR cells compared to RS cells suggesting a differential influence of PD-L1 on cell signaling. In summary, our data imply the need for different therapeutic strategies dependent on the molecular context in which PD-L1 is embedded.

Personalized Pain Goals and Responses in Advanced Cancer Patients.

To assess the personalized pain intensity goal (PPIG), the achievement of a personalized pain goal response (PPGR), and patients' global impression (PGI) in advanced cancer patients after a comprehensive pain and symptom management. Prospective, longitudinal. Acute pain relief and palliative/supportive care. 689 advanced cancer patients. Measurement of Edmonton Symptom Assessment Score (ESAS) and personalized pain intensity goal (PPIG) at admission (T0). After a week (T7) personalized pain goal response (PPGR) and patients' global impression (PGI) were evaluated. The mean PPIG was 1.33 (SD 1.59). A mean decrease in pain intensity of - 2.09 was required on PPIG to perceive a minimal clinically important difference (MCID). A better improvement corresponded to a mean change of - 3.41 points, while a much better improvement corresponded to a mean of - 4.59 points. Patients perceived a MCID (little worse) with a mean increase in pain intensity of 0.25, and a worse with a mean increase of 2.33 points. Higher pain intensity at T0 and lower pain intensity at T7 were independently related to PGI. 207 (30.0%) patients achieved PPGR. PPGR was associated with higher PPIG at T0 and T7, and inversely associated to pain intensity at T0 and T7, and Karnofsky level. Patients with high pain intensity at T0 achieved a favorable PGI, even when PPIG was not achieved by PPGR. PPIG, PPGR and PGI seem to be relevant for evaluating the effects of a comprehensive management of pain, assisting decision-making process according to patients' expectations. Some factors may be implicated in determining the individual target and the clinical response.

Personalized goal for insomnia and clinical response in advanced cancer patients.

The aim of this study was to assess the Personalized Insomnia Intensity Goal (PIIG), the achievement of Personalized Goal Response (PGR), and Patient Global Impression (PGI) after a comprehensive symptom management. Advanced cancer patients admitted to palliative care units rated pain and symptoms intensity and their PIIG by using the Edmonton Symptom Assessment Score (ESAS) (T0). In patients with significant levels of insomnia, the achievement of target expected (PIIG) was measured (patient goal response, PIGR), as well the patient global impression (PGI), by the minimal clinically important difference (MCID), after a comprehensive symptom management (T7). Three hundred ninety-seven patients with a level of insomnia of ≥ 3 on ESAS were analyzed in this study. The mean values of PIIG at T0 and T7 were 1.2 (SD 1.5) and 0.9 (SD 1.4), respectively. Most patients (n = 406, 89.8%) indicated a PIIG of ≤ 3 as a target at T0. Such target was significantly lower at T7 (p = < 0.0005). PGI, expressed as MCID, was perceived with a mean decrease in insomnia intensity of - 2.3. In a minority of patients (n = 26; 5.8%) insomnia worsened, with a MCID of 0.50 (SD 2.8). Higher insomnia intensity at T0 and lower insomnia intensity at T7 were independently related to PGI. PIGR was achieved in 87.9% of patients. PIGR was associated with PIIG at T0, and inversely associated to insomnia intensity at T0 and T7, and PIIG at T7. PGIR and PGI seem to be relevant for evaluating the effects of a comprehensive management of insomnia, suggesting therapeutic decisions according to PIIG. Some factors influencing the individual target and clinical response have been detected.

Personalized Goal for Dyspnea and Clinical Response in Advanced Cancer Patients

BackgroundThe clinical response after comprehensive symptom management is difficult to determine in terms of a clinically important difference. Moreover, therapies should try to reach the threshold perceived by the individual patient for the determination of a favorable response to a treatment. MeasuresThe Edmonton Symptom Assessment Score (ESAS) was measured at admission (T0), and seven days after starting palliative care (T7). Patient Global Impression and Goal Response after one week of palliative care and its relation with the Personalized Dyspnea Goal were measured at T7. InterventionPatients admitted to palliative care units underwent a comprehensive symptom assessment by a specialist palliative care team. At T0, patients were asked about their Personalized Dyspnea Intensity Goal on ESAS. One week later (T7), after a comprehensive palliative care treatment, Personalized Dyspnea Intensity Goals were measured again. Patients were considered to have achieved a Patient Dyspnea Goal Response if dyspnea intensity (measured at T7) was equal or less than their expected Personalized Dyspnea Intensity Goal. At the same interval (T7), Patient Global Impression (improvement or deterioration) was measured. Outcomes279 patients were analyzed in this study. The mean Personalized Dyspnea Intensity Goal at T0 and T7 were 0.97 (SD 1.3), and 0.71 (SD 2.1), respectively. 263 patients (94.2%) indicated a Personalized Dyspnea Intensity Goal of ≤3 as a target at T0. Patients perceived a bit better, a better improvement, and a much better improvement with a mean decrease in dyspnea intensity of -2.1, -3.5, and -4.3 points on the dyspnea intensity scale, respectively. In 60 patients (21.5%), dyspnea intensity did not change, and in 4.7%, dyspnea intensity worsened. Patients perceived a Minimal Clinically Important Difference (little worse) with a mean increase in dyspnea intensity of 0.10, and they perceived a worse with a mean increase of 1.7 points. Higher dyspnea intensity at T0 and lower dyspnea intensity at T7 were independently related to Patient Global Impression. At T7, 93 (33.3%) patients achieved their Personalized Goal Response, based on Personalized Dyspnea Intensity. Patient Dyspnea Goal Response was associated with Memorial Delirium Assessment Scale score and Personalized Dyspnea Intensity Goal at T0, and inversely associated with dyspnea intensity at T0 and T7, and lower Karnofsky level. For Patient Dyspnea Goal Response, no significant differences among categories of dyspnea intensity were found (P>0.05). ConclusionPatient Dyspnea Goal Response and Patient Global Impression seem to be relevant for evaluating the effects of a comprehensive management of symptoms, including dyspnea, assisting decision making process. Some factors may be implicated in determining the individual target and clinical response. A personalized symptom goal may translate in terms of therapeutic intervention, according to the achievement of the patients' expectations. High values of dyspnea intensity, a lower Karnofsky level, as well as high level of Dyspnea Intensity Goal (that is less patients' expectations) favor the achievement of the target.

Dynamic testing of positive and negative biomarkers on peripheral blood cells at early stages of immunotherapy predicts response in advanced cancer patients.

e15131Background: Immunotherapy against malignant tumors shows outstanding clinical efficacy, especially agents targeting the programmed death 1 (PD-1) pathway. In this study, we intended to dynami...

Immunotherapy and tumor microenvironment

Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases.

Abstract 4286: Development of a safe and effective systemically administered multiple Toll-like receptor (TLR) agonist for anti-tumor immunotherapy

Abstract Summary We have developed methods for detoxification and killing of Gram-negative bacteria, which significantly reduce both lipopolysaccharide (LPS) and non-LPS-mediated endotoxin activity and pyrogenicity, without compromising stimulation of anti-tumor immune responses. Background The field of cancer immunotherapy was founded in the late 1800s, based on the observation of tumor regression in the setting of bacterial infection. This was reproduced with intentionally administered live bacteria, but the approach was not safe due to infection and septic shock. A mixture of heat killed bacteria (Coley's toxins) produced long-term responses in advanced cancer patients over 100 years, but was apparently too toxic for safe intravenous (iv) administration at effective doses. In addition, lack of understanding of efficacy and toxicity mechanisms prevented optimization. Discovery of the role of TLRs in immune function has provided a mechanistic rationale for reconsideration of this approach. Gram-negative bacteria were required for the anti-tumor activity of Coley's toxins, due to the presence of multiple TLR agonists, including LPS, which is not produced by Gram-positive bacteria. However, too much TLR activation can over-stimulate the immune system, leading to toxicity. Attempts to produce live, attenuated Gram-negative bacteria for systemic cancer therapy have not been successful. A Phase 1 trial of one product produced dose-limiting symptoms of bacterial infection and septic shock, without evidence of antitumor activity. These historical observations suggest that a killed and appropriately attenuated Gram-negative product might produce significant anti-tumor activity if it could be administered safely iv. Methods and Results Non-pathogenic Gram-negative bacteria were treated with polymyxin B and glutaraldehyde. Endotoxin activity and pyrogenicity were quantified using Limulus amebocyte lysate (LAL) and rabbit pyrogenicity assays. Bacterial integrity was assessed by EM. Antitumor activity was determined using syngeneic tumors in mice. Treatment was found to kill the bacteria and reduce LPS-mediated endotoxin activity by ≥12-fold and non-specific pyrogenicity by ≥30-fold, with retention of cell integrity. The first product, DB103, was approximately 2,500-fold less toxic in mice than a previously described live, attenuated preparation, and produced significant dose-dependent in vivo antitumor activity at non-toxic doses. DB103 was also additive or synergistic in vivo when combined with each of four different established antitumor immunotherapies, including IL-2, metronomic cyclophosphamide, and anti-CTLA-4 or anti-GITR antibodies. Conclusions We have developed a multiple TLR agonist that can be safely and effectively administered systemically alone or in combination with a wide variety of existing anti-tumor immunotherapies. Citation Format: Michael J. Newman. Development of a safe and effective systemically administered multiple Toll-like receptor (TLR) agonist for anti-tumor immunotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2015-4286

Abstract 5017: T-cell repertoire turnover induced by anti-CTLA-4 antibody treatment in cancer patients

Abstract While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. We used a next-generation sequencing-based method to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher's exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Whereas the number of clonotypes that increased with treatment was not associated with clinical outcome, improved overall survival was associated with maintenance of high frequency clones present at baseline. In contrast the highest frequency clonotypes fell with treatment in patients with shorter overall survival. Stably maintained clonotypes included T cells possessing high avidity TCR such as CMV-reactive T cells. Together, these results suggest that CTLA-4 blockade induces T-cell repertoire evolution and diversification. Moreover, improved clinical outcomes are associated with less clonotype loss, consistent with the maintenance of high frequency TCR clonotypes during treatment. These clones may represent the presence of pre-existing high avidity T cells that may be relevant in the anti-tumor response. Citation Format: Lawrence H. Fong, Edward Cha, Mark Klinger, Yafei Hou, Craig Cummings, Antoni Ribas, Malek Faham. T-cell repertoire turnover induced by anti-CTLA-4 antibody treatment in cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2014-5017

Abstract 3695: The utility of plasma vascular endothelial growth factor and heparanase as pharmacodynamic markers following treatment with PG545, a heparan sulfate mimetic: preliminary evidence from preclinical and clinical settings

Abstract Background: The heparan sulfate mimetic PG545 has been demonstrated to inhibit the function of vascular endothelial growth factor (VEGF) and heparanase (HPSE) in vitro whilst downregulating HPSE expression in tumor and metastatic tissue in vivo. Although there are reports of consistent drug-induced increases in plasma VEGF with VEGF inhibitors such as bevacizumab, similar data are lacking for HS mimetics. Given PG545's mechanism of action which involves inhibition of both angiogenesis and metastasis, the evaluation of plasma VEGF and HPSE may represent pharmacodynamic (PD) biomarkers for each of these key processes. Materials and Methods: The levels of plasma VEGF and HPSE were measured using ELISA in samples from preclinical models of ovarian cancer (syngeneic ID8 and xenogeneic A2780 models) and a small cohort of patients (dosed with PG545 by the subcutaneous route) with advanced solid tumors from a Phase I clinical study. In tumor models, PG545 was administered once weekly by intravenous or intraperitoneal routes and efficacy was determined by quantifying tumor burden using the following methods: measurement of palpable solid tumors, abdominal circumference, ascites volume and/or by tracking cells using bioluminescent reporter imaging (depending on the model). In the A2780 model and the clinical samples, the pharmacokinetics of PG545 was also evaluated using LC-MS/MS, which ensured multiple samples to facilitate the measurement of VEGF and HPSE in plasma over the duration of the dosing interval following treatment with PG545. Results: PG545 demonstrated potent antitumor and antimetastatic activity when administered once weekly via intravenous or intraperitoneal routes in preclinical studies. These studies also indicated that PG545 treatment led to increases in plasma VEGF and HPSE. Importantly, plasma samples from advanced cancer patients treated with PG545 also revealed increases in these PD markers with initial peaks often correlating with Cmax of PG545 but longer-term gradual increases also noted in some instances. We consider that these increases in plasma levels result from PG545 binding to, thereby inhibiting, VEGF and HPSE in the tumor microenvironment. Conclusion: Given the questionable utility of single time point measures of plasma PD markers (including VEGF), these preliminary data suggest that kinetic profiling can reveal the previously undetermined dynamics of circulating VEGF and HPSE following treatment with PG545. Thus, the measurement of VEGF and HPSE appears to represent potential markers of pharmacodynamic activity. A new Phase I trial with intravenously-administered PG545 has recently commenced and should further clarify the potential utility of these basic PD biomarker responses in advanced cancer patients. Citation Format: Keith Dredge, Edward Hammond, Boris Winterhoff, Shailendra Giri, Attila Teoman, Darryn Bampton, Michael Millward, Viji Shridhar. The utility of plasma vascular endothelial growth factor and heparanase as pharmacodynamic markers following treatment with PG545, a heparan sulfate mimetic: preliminary evidence from preclinical and clinical settings. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3695. doi:10.1158/1538-7445.AM2014-3695

Association of maintenance of pre-existing memory T-cell responses following anti-CTLA-4 antibody treatment with improved overall survival.

3016 Background: While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, the immunobiology and biomarkers associated with improved clinical outcomes is ...

Evaluation of a novel blood pressure scoring method and its association with clinical response in cancer patients treated with anti-vascular endothelial growth factor therapy.

The purposes of this study were to establish a novel blood pressure (BP) scoring method and to correlate it with clinical response in advanced cancer patients treated with anti-vascular endothelial growth factor (VEGF) therapies. We retrospectively analyzed data for 368 patients from 23 clinical trials that included at least one anti-VEGF agent. We determined BP scores using the traditional Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and our novel method that considers both BP readings and number of anti-hypertensive medications the patient received. BP scores were categorized at baseline and four months. Logistic regression analysis correlated elevated scores with clinical response. Agreement between the CTCAE and the new method was assessed. Under the new BP scoring method, partial response rates were 20 % in patients with an elevated score at four months versus 6 % in patients without elevated score (P < 0.001). When adjusted for tumor type, age, sex, history of anti-VEGF treatment, and number of anti-VEGF treatments, elevated BP under the new scoring method had an odds ratio of 3.8 (95 % confidence interval [CI]: 1.8, 8.2; P < 0.001). The kappa statistic for agreement between the CTCAE and new scoring methods was 0.57 (95 % CI: 0.47, 0.67; P < 0.001), indicating significant concordance. Using the novel scoring method, an increase in BP scores was a marker for favorable clinical response in patients who received anti-VEGF treatment. This new method ultimately provides information with regard to clinical tumor response over and above that provided by the CTCAE scoring method.

Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy

Patients afflicted with advanced cancers were treated with the intratumoral injection of autologous immature dendritic cells (iDCs) followed by activated T-cell infusion and intensity-modulated radiation therapy (IMRT). A second round of iDCs and activated T cells was then administered to patients after the last radiation cycle. This complete regimen was repeated for new and recurring lesions after 6 weeks of follow-up. One year post therapy, outcome analyses were performed to evaluate treatment efficacy. Patients were grouped according to both the number and size of tumors and clinical parameters at treatment initiation, including recurrent disease after standard cancer therapy, Stage IV disease, and no prior therapy. Irrespective of prior treatment status, 23/37 patients with ≤ 5 neoplastic lesions that were ≤ 3 cm in diameter achieved complete responses (CRs), and 5/37 exhibited partial responses (PRs). Among 130 individuals harboring larger and more numerous lesions, CRs were observed in 7/74 patients that had received prior SCT and in 2/56 previously untreated patients. Some patients manifested immune responses including an increase in CD8+CD56+ lymphocytes among circulating mononuclear cells in the course of treatment. To prospectively explore the therapeutic use of these cells, CD8+ cells were isolated from patients that had been treated with cellular immunotherapy and IMRT, expanded in vitro, and injected into recurrent metastatic sites in 13 individuals who underwent the same immunoradiotherapeutic regimens but failed to respond. CRs were achieved in 34 of 58 of such recurrent lesions while PRs in 17 of 58. These data support the expanded use of immunoradiotherapy in advanced cancer patients exhibiting progressive disease.

Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients.

3020 Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencing-based method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.

Switching from oxycodone to methadone in advanced cancer patients

The aim of this study was to prospectively evaluate the outcomes and the conversion ratio of switching from oxycodone to methadone in advanced cancer patients admitted to an acute palliative care unit. A prospective study was carried out on a cohort of consecutive sample of patients receiving oxycodone, who were switched for different reasons mainly because of an inconvenient balance between analgesia and adverse effects. An initial conversion ratio between oxycodone and methadone was 3.3:1. Intensity of pain and symptoms associated with opioid therapy were recorded, and a distress score (DS) was also calculated as a sum of symptom intensity. A successful switching was considered when the intensity of pain and/or DS or the principal symptom requiring switching decreased at least of 33% of the value recorded before switching. Nineteen out of 542 patients admitted to the unit in 1 year underwent a switching from oxycodone to methadone. Almost all substitutions were successful. The prevalent indication for opioid switching was uncontrolled pain and adverse effects (12 patients). No significant changes between the initial conversion ratio and final conversion ratio between the two opioids were found. Switching from oxycodone to methadone is a reliable method to improve the opioid response in advanced cancer patients. A ratio of 3.3 appears to be reliable, even at high doses. Further studies should be performed to confirm these results in other settings and with very high doses of oxycodone.

Does pain intensity predict a poor opioid response in cancer patients?

Aim The aim of this study was to test the hypothesis that initial pain intensity is not a predictive factor of poor opioid response in advanced cancer patients, as suggested by a recent work. Methods A secondary analysis of one-hundred-sixty-seven patients referred for treatment of cancer-related pain was conducted. Pain intensity at admission was recorded and patients were divided in three categories of pain intensity: mild, moderate and severe. Patients were offered a treatment with opioid dose titration, according to department policy. Data regarding opioid doses and pain intensity were collected after dose titration was completed. Four levels of opioid response were considered: (a) good pain control, with minimal opioid escalation and without relevant adverse effects; (b) good pain control requiring more aggressive opioid escalation, for example doubling the doses in four days; (c) adequate pain control associated with the occurrence of adverse effects; (d) poor pain control with adverse effects. Results Seventy-six, forty-four, forty-one and six patients showed a response a, b, c, and d, respectively. No correlation between baseline pain intensity categories and opioid response was found. Patients with response ‘b’ and ‘d’ showed higher values of OEI mg. Conclusion Baseline pain intensity does not predict the outcome after an appropriate opioid titration. It is likely that non-homogeneous pain treatment would have biased the outcome of a previous work.