Chimeric Antigen Receptor Immunotherapy for Solid Tumors: Choosing the Right Ingredients for the Perfect Recipe

Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development

Intratumoral injection of IFN-alpha dendritic cells after dacarbazine activates anti-tumor immunity: Results from a phase I trial in advanced melanoma

Background: Advanced melanoma patients have an extremely poor long term prognosis and are in strong need of new therapies. The recently developed targeted therapies have resulted in a marked antitumor effect, but most responses are partial and some degree of toxicity remain the major concerns. Methods: We tested in a phase I clinical study in advanced melanoma a chemo-immunotherapy approach based on unloaded IFN-DCs injected intratumorally one day after administration of dacarbazine. Primary endpoint of the study was treatment safety and tolerability. Secondary endpoints were immune and clinical responses of patients. Results: Six patients were enrolled, and only three completed the treatment. The chemo-immunotherapy was well tolerated with no major side effects. Three patients showed temporary disease stabilization and two of them showed induction of T cells specific for tyrosinase, NY-ESO-1 and gp100. Of interest, one patient showing a remarkable long-term disease stabilization kept showing presence of tyrosinase specific T cells in PBMC and high infiltration of memory T cells in the tumor lesion at 21 months. Conclusion: We tested a chemo-immunotherapeutic approach based on IFN-DCs injected intratumorally one day after DTIC in advanced melanoma. The treatment was well tolerated, and clinical and immunological responses, including development of vitiligo, were observed, therefore warranting additional clinical studies aimed at evaluating efficacy of this approach

Clinical and antitumor immune responses In Relapsed/Refractory Follicular Lymphoma patients after intranodal injections of IFNα-Dendritic Cells and Rituximab

This study was aimed at evaluating the feasibility, safety, immunological and clinical responses in patients with Follicular lymphoma (FL) treated with monocyte-derived dendritic cells generated in the presence of interferon-alpha and GM-CSF (IFN-DC) in combination with low doses of Rituximab (R).Firstly, we analyzed in vitro and in vivo the immunological properties of IFN-DC against FL. Thus, we performed a phase I trial in 8 refractory and relapsed FL patients based on sequential intranodal injections of low-dose of R and unloaded IFN-DC and report the safety, clinical and immunological results of the enrolled patients.Preclinical studies indicated that IFN-DC can synergize with R leading to increased cytotoxicity and T cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37% and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T cell responses by CD107 degranulation or IFN-g ELISPOT assay against patient-specific tumor IGHV sequences.These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in cancer patients

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: The Pros-IT CNR study

BACKGROUND: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. METHODS: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). RESULTS: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. CONCLUSIONS: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the Pros-IT CNR study

Background: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. Methods: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). Results: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Conclusions: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care

Pros-IT CNR: an Italian prostate cancer monitoring project

Aims: The Pros-IT CNR project aims to monitor a sample of Italian males \ue2\u89\ua518\uc2 years of age who have been diagnosed in the participating centers with incident prostate cancer, by analyzing their clinical features, treatment protocols and outcome results in relation to quality of life. Methods: Pros-IT CNR is an observational, prospective, multicenter study. The National Research Council (CNR), Neuroscience Institute, Aging Branch (Padua) is the promoting center. Ninety-seven Italian centers located throughout Italy were involved. The field study began in September 1, 2014. Subjects eligible were diagnosed with biopsy-verified prostate cancer, na\uc3\uafve. A sample size of 1500 patients was contemplated. A baseline assessment including anamnestic data, clinical history, risk factors, the initial diagnosis, cancer staging information and quality of life (Italian UCLA Prostate Cancer Index; SF-12 Scale) was completed. Six months after the initial diagnosis, a second assessment evaluating the patient\ue2\u80\u99s health status, the treatment carried out, and the quality of life will be made. A third assessment, evaluating the treatment follow-up and the quality of life, will be made 12\uc2 months after the initial diagnosis. The 4th, 5th, 6th and 7th assessments, similar to the third, will be completed 24, 36, 48 and 60\uc2 months after the initial diagnosis, respectively, and will include also a Food Frequency Questionnaire and the Physical Activity Scale for the Elderly. Discussion: The study will provide information on patients\ue2\u80\u99 quality of life and its variations over time in relation to the treatments received for the prostate cancer