Transient TCR-based T cell therapy in a patient with advanced treatment-resistant MSI-high colorectal cancer.

We previously demonstrated the antitumor effectiveness of transiently T cell receptor (TCR)-redirected T cells recognizing a frameshift mutation in transforming growth factor beta receptor 2. We here describe a clinical protocol using mRNA TCR-modified T cells to treat a patient with progressive, treatment-resistant metastatic microsatellite instability-high (MSI-H) colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in-vitro-transcribed Radium-1 TCR mRNA, we assessed T cell cytotoxicity, phenotype, and cytokine production. Tumor markers and growth on computed tomography scans were evaluated and immune cell tumor infiltrate at diagnosis assessed. At diagnosis, tumor-infiltrating CD8+ T cells had minimal expression of exhaustion markers, except for PD-1. Injected Radium-1 T cells were mainly naive and effector memory T cells with low expression of exhaustion markers, except for TIGIT. We confirmed cytotoxicity of transfected Radium-1 T cells against target cells and found key cytokines involved in tumor metastasis, growth, and angiogenesis to fluctuate during treatment. The treatment was well tolerated, and despite his advanced cancer, the patient obtained a stable disease with 6 months survival post-treatment. We conclude that treatment of metastatic MSI-H colorectal cancer with autologous T cells electroporated with Radium-1 TCR mRNA is feasible, safe, and well tolerated and that it warrants further investigation in a phase 1/2 study.

Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma.

Advanced stage follicular lymphoma (FL) is incurable by conventional therapies. In the present pilot clinical trial, we explored the efficacy and immunogenicity of a novel in situ immunotherapeutic strategy. Fourteen patients with untreated or relapsed stage III/IV FL were included and received local radiotherapy to solitary lymphoma nodes and intranodal injections of low-dose rituximab (5 mg), immature autologous dendritic cells, and granulocyte-macrophage colony-stimulating factor at the same site. The treatment was repeated 3 times targeting different lymphoma nodes. Primary end points were clinical responses and induction of systemic immunity. Five out of 14 patients (36%) displayed objective clinical responses, including 1 patient with cutaneous FL who showed regression of skin lesions. Two of the patients had durable complete remissions. Notably, the magnitude of vaccination-induced systemic CD8 T-cell-mediated responses correlated closely with reduction in total tumor area (r = 0.71, P = .006), and immune responders showed prolonged time to next treatment. Clinical responders did not have a lower tumor burden than nonresponders pretreatment, suggesting that the T cells could eliminate large tumor masses once immune responses were induced. In conclusion, the combined use of 3 treatment modalities, and in situ administration in single lymphoma nodes, mediated systemic T-cell immunity accompanied by regression of disseminated FL. The trial was registered at www.clinicaltrials.gov as #NCT01926639.

Diffusion-weighted MRI compared to FDG PET/CT for assessment of early treatment response in lymphoma.

BACKGROUND: 18F fluoro-deoxyglucose (FDG) positron emission tomography / computed tomography (PET/CT) is a well-recognized diagnostic tool used for staging and monitoring of therapy response for lymphomas. During the past decade diffusion-weighted (DW) magnetic resonance imaging (MRI) is increasingly being included in the assessment of tumor response for various cancers. PURPOSE: To compare the change in maximum standardized uptake value (ΔSUVmax) from FDG PET/CT with the change in apparent diffusion coefficient (ΔADC) from DW MRI after initiation of the first cycle of chemotherapy in patients with Hodgkin's lymphoma (HL) and in patients with diffuse large B-cell lymphoma (DLBCL). MATERIAL AND METHODS: Twenty-seven consecutive patients with histologically proven lymphoma and lymphomatous lymph nodes (LLN) of the neck (19 with HL, 8 with DLBCL) underwent FDG PET/CT and MRI of the neck before and after initiation of the first cycle of chemotherapy. The mean time interval from initiation of chemotherapy to imaging was 19 days and 2 days for FDG PET/CT and MRI, respectively. For each patient ΔSUVmax, ΔADC, and change in volume of the same LLN were compared. RESULTS: There was a significant mean decrease of SUVmax by 70%, but no significant change in ADC. There was no significant reduction in LLN volume. CONCLUSION: There was no significant correlation between ΔSUVmax and ΔADC. Thus, our data do not support that FDG PET/CT can be replaced by early DW MRI for response evaluation in lymphoma patients.

Enhancement characteristics of retroperitoneal lymphomatous lymph nodes.

BACKGROUND: Previous studies of CT enhancement of lymphomatous lymph nodes (LLN) of the neck and the mediastinum showed that the LLN had lower enhancement values than normal lymph nodes. PURPOSE: To elucidate the contrast medium enhancement curves of LLN in the retroperitoneum by comparing the curves of LLN with those of normal lymph nodes, to test whether differences between these curves could be of diagnostic value, and to compare the present enhancement curves of LLN of the retroperitoneum with the curves of LLN of the neck and the mediastinum from previous similar investigations. MATERIAL AND METHODS: Twenty-eight consecutive patients with LLN of the retroperitoneum (three with Hodgkin's lymphoma [HL]) and 21 control patients with sarcomas and thus presumably normal retroperitoneal nodes underwent dynamic CT examinations. The previous, similar investigation of lymph nodes of the neck comprised 28 patients with LLN and the investigation of mediastinal lymph nodes comprised 24 patients with LLN. RESULTS: The enhancement curves of the retroperitoneal LLN had significantly lower attenuation than those of the retroperitoneal control nodes. A combination of peak contrast value and time to peak adjusted to total body weight yielded a diagnostic accuracy which at the best showed a sensitivity of 90.5% with a specificity of 82.6%. The LLN of the retroperitoneum had higher attenuation values than corresponding nodes of the mediastinum but no significant difference was found between LLN of the retroperitoneum and LLN of the neck in previous similar investigations. CONCLUSION: The comparison of enhancement curves of retroperitoneal LLN with retroperitoneal control nodes showed a marked similarity with and substantiates our previous findings in lymph nodes of the neck and of the mediastinum. The best diagnostic accuracy was achieved by combining the parameters peak contrast value and time to peak and adjusting these values to the body weight. Peak enhancement of the retroperitoneal LLN was higher and arrived earlier than that of the mediastinal nodes from the previous investigation.

Enhancement characteristics of lymphomatous lymph nodes of the mediastinum.

BACKGROUND: Previous studies of CT enhancement of lymphomatous lymph nodes (LLN) of the neck showed that the LLN had lower enhancement values than normal lymph nodes. PURPOSE: To elucidate the contrast medium enhancement curves of LLN in the mediastinum by comparing the curves of LLN with those of normal lymph nodes, and to compare the present enhancement curves of LLN of the mediastinum with the curves of LLN of the neck from a previous similar investigation. MATERIAL AND METHODS: Twenty-four consecutive patients with LLN in the mediastinum (9 with Hodgkin's lymphoma [HL]) and 23 control patients with sarcomas and thus presumably normal mediastinal nodes underwent dynamic CT examinations. The previous, similar investigation of lymph nodes of the neck comprised 28 patients with LLN and 20 control patients. RESULTS: The enhancement curves of the mediastinal LLN had significantly lower values than those of the mediastinal control nodes. The LLN of the mediastinum had lower mean peak contrast values than the corresponding nodes of the neck from a previous investigation. CONCLUSION: The comparison of enhancement curves of mediastinal LLN with mediastinal control nodes showed a marked similarity with and substantiates our previous findings in lymph nodes of the neck.

Enhancement characteristics of lymphomatous lymph nodes of the neck.

BACKGROUND: Previous studies of computed tomography (CT) enhancement of lymphomatous lymph nodes suggest that these nodes might have lower post contrast attenuation values than normal lymph nodes. We have previously found that the contrast medium enhancement curves of lymphomatous lymph nodes of the neck had significantly lower enhancement than those of presumably normal lymph nodes. PURPOSE: To prospectively compare CT contrast medium enhancement curves of a homogeneous population of 28 patients with lymphomatous lymph nodes of the neck with 20 controls; to compare enhancement curves before and after successful treatment and to compare nodes with Hodgkin lymphoma (HL) and nodes with non-Hodgkin lymphoma (NHL). MATERIAL AND METHODS: Twenty-eight consecutive patients (12 with HL) with lymphomatous lymph nodes of the neck and 20 control patients with sarcomas and presumably normal neck nodes underwent dynamic CT examinations. Seventeen of the patients in complete remission after lymphoma treatment were also examined. RESULTS: The lymphomatous lymph nodes had significantly lower mean enhancement values than those of the control group (mean HU value at 90 s 77.9+/-10.5 HU and 93.4+/-15.3 HU, respectively, sensitivity 91% for values <92 HU at 90 s). Late enhancement values in the treated patients were significantly higher than those in the untreated patients. Patients with HL and patients with NHL had similar enhancement curves except that those with NHL had higher values at 7 min. No significant difference in mean percentage loss of enhancement was found between normal nodes and lymph nodes with HL before treatment, but there was a slightly significant difference between normal nodes and lymph nodes with NHL. No significant difference in percentage loss of enhancement was found between normal nodes and lymphomatous lymph nodes after treatment. CONCLUSION: Dynamic CT examinations showed that lymphomatous lymph nodes had significantly lower mean enhancement values than those of the control group and confirmed the findings from a pilot study. Before treatment the mean enhancement values of HL were significantly higher than those of NHL at 7 min. There was no significant difference between the curves after treatment.

[Sinus radiography and low-dose CT in the diagnosis of acute sinusitis. ]. / Røntgen bihuler og lavdose-CT ved akutt sinusitt.

Background. Although CT is considered the method of choice in the evaluation of inflammatory sinus disease, plain film radiography is still used, as repetitive CT examinations may impart a considerable radiation dose to the lens. We designed a new low-dose CT examination and compared this and plain film radiography to standard-dose CT. Methods and materials. The new CT low-dose protocol consisted of ten coronal scans at 40 mAs and 1 mm collimation. 47 patients referred for acute sinusitis were examined with plain film radiography, low-dose and standard-dose CT on the same day. The latter was used as "the gold standard". Results. The sensitivity of plain film radiography was low (< 50 %) except for the maxillary sinus (80 %). The overall sensitivity of low-dose CT was 95 % and the specificity 97 %. Effective dose and lens dose of low-dose CT were 3 % and 2 % respectively compared to standard-dose CT. Corresponding values for conventional radiography were 13 % and 2 %. Interpretation. Low-dose CT had image quality comparable to standard-dose CT and a dose to the eye lens equal to plain film radiography. Low-dose CT should be the method of choice in patients referred for acute sinusitis.