Artificial intelligence in immunotherapy PET/SPECT imaging.

OBJECTIVE: Immunotherapy has dramatically altered the therapeutic landscape for oncology, but more research is needed to identify patients who are likely to achieve durable clinical benefit and those who may develop unacceptable side effects. We investigated the role of artificial intelligence in PET/SPECT-guided approaches for immunotherapy-treated patients. METHODS: We performed a scoping review of MEDLINE, CENTRAL, and Embase databases using key terms related to immunotherapy, PET/SPECT imaging, and AI/radiomics through October 12, 2022. RESULTS: Of the 217 studies identified in our literature search, 24 relevant articles were selected. The median (interquartile range) sample size of included patient cohorts was 63 (157). Primary tumors of interest were lung (n = 14/24, 58.3%), lymphoma (n = 4/24, 16.7%), or melanoma (n = 4/24, 16.7%). A total of 28 treatment regimens were employed, including anti-PD-(L)1 (n = 13/28, 46.4%) and anti-CTLA-4 (n = 4/28, 14.3%) monoclonal antibodies. Predictive models were built from imaging features using univariate radiomics (n = 7/24, 29.2%), radiomics (n = 12/24, 50.0%), or deep learning (n = 5/24, 20.8%) and were most often used to prognosticate (n = 6/24, 25.0%) or describe tumor phenotype (n = 5/24, 20.8%). Eighteen studies (75.0%) performed AI model validation. CONCLUSION: Preliminary results suggest broad potential for the application of AI-guided immunotherapy management after further validation of models on large, prospective, multicenter cohorts. CLINICAL RELEVANCE STATEMENT: This scoping review describes how artificial intelligence models are built to make predictions based on medical imaging and explores their application specifically in the PET and SPECT examination of immunotherapy-treated cancers. KEY POINTS: • Immunotherapy has drastically altered the cancer treatment landscape but is known to precipitate response patterns that are not accurately accounted for by traditional imaging methods. • There is an unmet need for better tools to not only facilitate in-treatment evaluation but also to predict, a priori, which patients are likely to achieve a good response with a certain treatment as well as those who are likely to develop side effects. • Artificial intelligence applied to PET/SPECT imaging of immunotherapy-treated patients is mainly used to make predictions about prognosis or tumor phenotype and is built from baseline, pre-treatment images. Further testing is required before a true transition to clinical application can be realized.

FDG PET/CT Imaging 1 Week after a Single Dose of Pembrolizumab Predicts Treatment Response in Patients with Advanced Melanoma.

PURPOSE: Immunologic response to anti-programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response. PATIENTS AND METHODS: Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled. FDG PET/CT imaging was performed at baseline and approximately 1 week after starting treatment. FDG PET/CT scans were evaluated for changes in maximum standardized uptake value (SUVmax) and thresholds were identified by ROC analysis; MF was defined as >70% increase in tumor SUVmax, and MR as >30% decrease in tumor SUVmax. RESULTS: An MF or MR was identified in 6 of 11 (55%) responders and 0 of 8 (0%) nonresponders, with an objective response rate (ORR) of 100% in the MF-MR group and an ORR of 38% in the stable metabolism (SM) group. An MF or MR was associated with T-cell reinvigoration in the peripheral blood and immune infiltration in the tumor. Overall survival at 3 years was 83% in the MF-MR group and 62% in the SM group. Median progression-free survival (PFS) was >38 months (median not reached) in the MF-MR group and 2.8 months (95% confidence interval, 0.3-5.2) in the SM group (P = 0.017). CONCLUSIONS: Early FDG PET/CT can identify metabolic changes in melanoma metastases that are potentially predictive of response to pembrolizumab and significantly correlated with PFS.

68 Ga-DOTATATE PET to Characterize Lesions in the Neuroaxis.

AIM: The differentiation of paragangliomas, schwannomas, meningiomas, and other neuroaxis tumors in the head and neck remains difficult when conventional MRI is inconclusive. This study assesses the utility of 68 Ga-DOTATATE PET/CT as an adjunct to hone the diagnosis. PATIENTS AND METHODS: This retrospective study considered 70 neuroaxis lesions in 52 patients with 68 Ga-DOTATATE PET/CT examinations; 22 lesions (31%) had pathologic confirmation. Lesions were grouped based on pathological diagnosis and best radiologic diagnosis when pathology was not available. Wilcoxon rank sum tests were used to test for differences in SUV max among paragangliomas, schwannomas, and meningiomas. Receiver operator characteristic curves were constructed. RESULTS: Paragangliomas had a significantly greater 68 Ga-DOTATATE uptake (median SUV max , 62; interquartile range [IQR], 89) than nonparagangliomas. Schwannomas had near-zero 68 Ga-DOTATATE uptake (median SUV max , 2; IQR, 1). Intermediate 68 Ga-DOTATATE uptake was seen for meningiomas (median SUV max , 19; IQR, 6) and other neuroaxis lesions (median SUV max , 7; IQR, 9). Receiver operator characteristic analysis demonstrated an area under the curve of 0.87 for paragangliomas versus all other lesions and 0.97 for schwannomas versus all other lesions. CONCLUSIONS: Marked 68 Ga-DOTATATE uptake (>50 SUV max ) favors a diagnosis of paraganglioma, although paragangliomas exhibit a wide variability of uptake. Low to moderate level 68 Ga-DOTATATE uptake is nonspecific and may represent diverse pathophysiology including paraganglioma, meningioma, and other neuroaxis tumors but essentially excludes schwannomas, which exhibited virtually no uptake.

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop.

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

Monitoring Therapeutic Response to Anti-FAP CAR T Cells Using [18F]AlF-FAPI-74.

PURPOSE: Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T-targeted antigens in tumors and accurate monitoring of response. EXPERIMENTAL DESIGN: We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer. RESULTS: [18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses. CONCLUSIONS: This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy. See related commentary by Weber et al., p. 5241.

Using CD69 PET Imaging to Monitor Immunotherapy-Induced Immune Activation.

ABSTRACT: Immune checkpoint inhibitors (ICI) have been effective in treating a subset of refractory solid tumors, but only a small percentage of treated patients benefit from these therapies. Thus, there is a clinical need for reliable tools that allow for the early assessment of response to ICIs, as well as a preclinical need for imaging tools that aid in the future development and understanding of immunotherapies. Here we demonstrate that CD69, a canonical early-activation marker expressed on a variety of activated immune cells, including cytotoxic T cells and natural killer (NK) cells, is a promising biomarker for the early assessment of response to immunotherapies. We have developed a PET probe by radiolabeling a highly specific CD69 mAb, H1.2F3, with Zirconium-89 (89Zr), [89Zr]-deferoxamine (DFO)-H1.2F3. [89Zr]-DFO-H1.2F3 detected changes in CD69 expression on primary mouse T cells in vitro and detected activated immune cells in a syngeneic tumor immunotherapy model. In vitro uptake studies with [89Zr]-DFO-H1.2F3 showed a 15-fold increase in CD69 expression for activated primary mouse T cells, relative to untreated resting T cells. In vivo PET imaging showed that tumors of ICI-responsive mice had greater uptake than the tumors of nonresponsive and untreated mice. Ex vivo biodistribution, autoradiography, and IHC analyses supported the PET imaging findings. These data suggest that the CD69 PET imaging approach detects CD69 expression with sufficient sensitivity to quantify immune cell activation in a syngeneic mouse immunotherapy model and could allow for the prediction of therapeutic immune responses to novel immunotherapies.

PSMA-targeting TGFß-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-ß. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-ß receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-ß-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET Images of Ovarian Cancer.

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of 18F-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of 18F-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing 18F-fluorthanatrace as a biomarker of response to PARPi therapy. Methods: Fourteen prospectively enrolled ovarian cancer patients were injected with 18F-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUVmax and SUVpeak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (n = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. Results:18F-fluorthanatrace blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. The total distribution volume from a reversible 2-tissue-compartment model and Logan reference tissue distribution volume ratio (DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (r = 0.76 and 0.83, respectively; P < 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUVmax and SUVpeak acquired from images with midpoints of 57.5, 110 ± 3, and 199 ± 4 min highly correlated with PARP-1 expression (mean ± SD, r ≥ 0.79; P < 0.05). Conclusion: Tumor SUVmax and SUVpeak at 55-60 min after injection and later and DVR from at least 60 min appear to be robust noninvasive measures of PARP-1 binding. 18F-fluorthanatrace uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.

CD8-Targeted PET Imaging of Tumor-Infiltrating T Cells in Patients with Cancer: A Phase I First-in-Humans Study of 89Zr-Df-IAB22M2C, a Radiolabeled Anti-CD8 Minibody.

There is a need for in vivo diagnostic imaging probes that can noninvasively measure tumor-infiltrating CD8+ leukocytes. Such imaging probes could be used to predict early response to cancer immunotherapy, help select effective single or combination immunotherapies, and facilitate the development of new immunotherapies or immunotherapy combinations. This study was designed to optimize conditions for performing CD8 PET imaging with 89Zr-Df-IAB22M2C and determine whether CD8 PET imaging could provide a safe and effective noninvasive method of visualizing the whole-body biodistribution of CD8+ leukocytes. Methods: We conducted a phase 1 first-in-humans PET imaging study using an anti-CD8 radiolabeled minibody, 89Zr-Df-IAB22M2C, to detect whole-body and tumor CD8+ leukocyte distribution in patients with metastatic solid tumors. Patients received 111 MBq of 89Zr-Df-IAB22M2C followed by serial PET scanning over 5-7 d. A 2-stage design included a dose-escalation phase and a dose-expansion phase. Biodistribution, radiation dosimetry, and semiquantitative evaluation of 89Zr-Df-IAB22M2C uptake were performed in all patients. Results: Fifteen subjects with metastatic melanoma, non-small cell lung cancer, and hepatocellular carcinoma were enrolled. No drug-related adverse events or abnormal laboratory results were noted except for a transient increase in antidrug antibodies in 1 subject. 89Zr-Df-IAB22M2C accumulated in tumors and CD8-rich tissues (e.g., spleen, bone marrow, nodes), with maximum uptake at 24-48 h after injection and low background activity in CD8-poor tissues (e.g., muscle and lung). Radiotracer uptake in tumors was noted in 10 of 15 subjects, including 7 of 8 subjects on immunotherapy, 1 of 2 subjects on targeted therapy, and 2 of 5 treatment-naïve subjects. In 3 patients with advanced melanoma or hepatocellular carcinoma on immunotherapy, posttreatment CD8 PET/CT scans demonstrated increased 89Zr-Df-IAB22M2C uptake in tumor lesions, which correlated with response. Conclusion: CD8 PET imaging with 89Zr-Df-IAB22M2C is safe and has the potential to visualize the whole-body biodistribution of CD8+ leukocytes in tumors and reference tissues, and may predict early response to immunotherapy.

Immune PET Imaging.

Fluorodeoxyglucose (FDG) PET/CT is sensitive to metabolic, immune-related, and structural changes that can occur in tumors in cancer immunotherapy. Unique mechanisms of immune checkpoint inhibitors (ICIs) occasionally make response evaluation challenging, because tumors and inflammatory changes are both FDG avid. These response patterns and sequelae of ICI immunotherapy, such as immune-related adverse events, are discussed. Immune-specific PET imaging probes at preclinical stage or in early clinical trials, which may help guide clinical management of cancer patients treated with immunotherapy and likely have applications outside of oncology for other diseases in which the immune system plays a role, are reviewed.

18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Following Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a well-established imaging modality to assess responses in patients with B-cell neoplasms. However, there is limited information about the utility of FDG PET/CT after chimeric antigen receptor T-cell (CART) therapies for large B-cell lymphomas. In this retrospective analysis, we aimed to evaluate how FDG PET/CT performs in patients receiving commercially available anti-CD19 CART therapies for relapsed/refractory (r/r) large B-cell lymphomas. In addition, we examined the time to repeat scan and the rate of pseudoprogression within this population. Lastly, the rates of radiographic response to CART therapy using FDG PET/CT are reported. PROCEDURES: The pre-treatment and post-treatment scans were analyzed from a selected cohort of 43 patients from a single institution. Patients were stratified by diagnosis of either a first occurrence of diffuse large B-cell lymphoma: de novo diffuse large B-cell lymphoma (DLBCL); or a transformed diffuse large B-cell lymphoma arising from indolent non-Hodgkin lymphoma (t-iNHL). RESULTS: More patients received CART therapy for DLBCL than t-iNHL (65 % vs 35 %). FDG PET/CT had a 99 % sensitivity and 100 % specificity for detecting recurrent disease in this group. The median time to initial response assessment was 86 days (IQR 79-91; full range 24-146) after infusion. There were no biopsy-proven cases of pseudoprogression identified. In this selected group of patients, the overall response rate by Lugano 2014 criteria was 56 %. All patients with a partial response (N = 6) eventually progressed despite additional therapy. CONCLUSIONS: Due to its excellent test characteristics and ability to detect asymptomatic disease, routine surveillance with PET/CT at 3 months after CART infusion is supported by our data. Earlier PET/CT may be of value in select situations as we did not find any cases of pseudoprogression.

In vivo visualization of PARP inhibitor pharmacodynamics.

BACKGROUND[18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODSTwo single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTSThirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION[18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATIONClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDINGMetavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.

Breast Cancer 18F-ISO-1 Uptake as a Marker of Proliferation Status.

The σ2 receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide (18F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of 18F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether 18F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Methods: Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of 18F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of 18F-ISO-1 was quantitated by SUVmax and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Results: Tumor SUVmax (median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUVmax, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUVmax greater than the low-Ki-67 (<20%) group (P = 0.02). SUVmax exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46, P = 0.01, n = 29). Partial-volume-corrected SUVmax was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51, P = 0.02, n = 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (P > 0.05). Conclusion:18F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.

Imaging CAR T Cell Trafficking with eDHFR as a PET Reporter Gene.

Cell-based therapeutics have considerable promise across diverse medical specialties; however, reliable human imaging of the distribution and trafficking of genetically engineered cells remains a challenge. We developed positron emission tomography (PET) probes based on the small-molecule antibiotic trimethoprim (TMP) that can be used to image the expression of the Escherichia coli dihydrofolate reductase enzyme (eDHFR) and tested the ability of [18F]-TMP, a fluorine-18 probe, to image primary human chimeric antigen receptor (CAR) T cells expressing the PET reporter gene eDHFR, yellow fluorescent protein (YFP), and Renilla luciferase (rLuc). Engineered T cells showed an approximately 50-fold increased bioluminescent imaging signal and 10-fold increased [18F]-TMP uptake compared to controls in vitro. eDHFR-expressing anti-GD2 CAR T cells were then injected into mice bearing control GD2- and GD2+ tumors. PET/computed tomography (CT) images acquired on days 7 and 13 demonstrated early residency of CAR T cells in the spleen followed by on-target redistribution to the GD2+ tumors. This was corroborated by autoradiography and anti-human CD8 immunohistochemistry. We found a high sensitivity of detection for identifying tumor-infiltrating CD8 CAR T cells, ∼11,000 cells per mm3. These data suggest that the [18F]-TMP/eDHFR PET pair offers important advantages that could better allow investigators to monitor immune cell trafficking to tumors in patients.

Prevalence and quantitative analysis of indium-111 pentetreotide (Octreoscan) uptake in the pancreatic head on SPECT/CT imaging: establishing a region of interest-based pathological uptake threshold.

OBJECTIVE: Determine the prevalence of benign indium-111 (In) pentetreotide uptake in the pancreatic head and determine if a semi-quantitative method can be used to differentiate physiologic from pathologic uptake. PATIENTS AND METHODS: Institutional Review Board-approved, HIPAA-compliant retrospective review of 197 somatostatin receptor scintigraphy studies performed in 136 patients, from December 2012 to November 2013 at a large academic medical center. The pancreatic head uptake was visually graded and for all positive cases, two-dimensional and three-dimensional ratios of the pancreatic head to normal liver uptake were calculated. Statistical analysis using paired and two-sample t-tests was performed. RESULTS: Nineteen of one hundred twenty-nine (14.7%) patients had benign In pentetreotide uptake in the pancreatic head. Seven of seven (100%) patients with neuroendocrine (NE) tumors had definite visual uptake. Uptake was 2.7× more likely benign than malignant. Using a three-dimensional region of interest (ROI) method, the pancreatic head-to-liver ratio was 0.91±0.38 (0.37-1.63) for benign uptake and 8.2±7.3 (1.79-23.6) for pathologic uptake (P<0.001). A threshold of 1.67 provided 100% accuracy for determining the presence or absence of a pancreatic head NE tumor. Using a two-dimensional ROI method, the uptake ratio was 0.88±0.37 (0.28-1.73) for benign and 7.5±6.2 (1.85-19.6) for pathologic uptake (P<0.001); a ratio threshold of 1.62 provided 97% accuracy. There was no difference between the uptake ratios at 4 and 24 h. CONCLUSION: In pentetreotide uptake in the pancreatic head is common and more frequently benign than malignant. Using simple ROI ratiometric methods helps to differentiate benign physiologic from malignant NE tumor uptake.

A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.

Early positron emission tomography/computed tomography as a predictor of response after CTL019 chimeric antigen receptor -T-cell therapy in B-cell non-Hodgkin lymphomas.

Molecular imaging with 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is an established modality for response assessment in patients with lymphoma undergoing treatment. However, patients treated with novel immunotherapies may have false-positive PET/CT findings due to tumor site and systemic inflammation. In particular, treatment with autologous chimeric antigen receptor modified T-cells redirected at CD19 (CTL019 CAR-T cells) is often complicated by "cytokine release syndrome" (CRS) due to a severe systemic inflammatory reaction. Infiltration of tumors by activated CTL019 cells may impact radiographic and functional imaging findings. The role of PET/CT in patients treated with CTL019 has not previously been described. We performed a pilot, single-arm, prospective study to explore the utility of early PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) undergoing treatment with CTL019 CAR-T cells. Patients had PET/CT prior to CTL019 infusion and then early PET/CT at 1 month after treatment. The primary outcome was the amount/change in metabolically active tumor volume (MTV) and FDG uptake. We enrolled seven patients (DLBCL, three; FL, four). Six of 7 had baseline PET/CT with active disease. On post-treatment PET/CT, three patients had no residual MTV, two patients had a decrease in MTV and two patients had an increase in MTV. The three patients with no residual MTV all remain in remission >2 years post-treatment. The patients with less than complete response all subsequently relapsed. Development of CRS did not confound PET/CT findings. In patients with DLBCL and FL receiving CTL019 CAR-T cells, early PET/CT may predict response to this novel immunotherapy.

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours.

BACKGROUND: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. METHODS: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. RESULTS: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. CONCLUSIONS: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. CLINICAL TRIAL REGISTRATION: NCT02303990 ( www.clinicaltrials.gov ).