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Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell–infiltrated tumors.Significance:Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1

Supplementary Figure from Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Supplementary Data from Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Supplementary Table from Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

4515 Background: SAKK 06/17 investigated the addition of perioperative immunotherapy with the anti-PD-L1 antibody durvalumab (Durva) in the multimodality treatment of resectable MIUC. While most similar trials had a primary endpoint of pathological complete remission rate, this study evaluated the clinically more relevant primary endpoint of event-free survival (EFS) at 2 years (yrs). Methods: SAKK 06/17 was an open-label, single-arm phase II study including 61 cisplatin-fit patients (pts) with stage cT2-T4a cN0-1 operable MIUC. Pts received four cycles of neoadjuvant Cis/Gem q3w in combination with 4 cycles Durva 1500mg q3w followed by complete resection. Adjuvant Durva 1500mg q4w was given for 10 cycles or a maximum of 40 weeks. The primary endpoint was EFS at 2 yrs after neoadjuvant trial treatment (NAT) start. An event was defined as progression during NAT, appearance of metastases, locoregional recurrence after surgery or death from any cause. 58 pts were needed based on one-sided type I error 10% and power 80% for H1 EFS at 2 yrs ≥ 65% compared to H0 EFS at 2 yrs ≤ 50%. Secondary endpoints included pathological response, recurrence free survival after R0 resection (RFS), overall survival (OS) and safety. We report the primary analysis of the full analysis set (FAS, received at least one dose of Durva). Results: 61 pts were included between July 2018 and September 2019 at 12 sites. Median follow up is 28.1 months (95%CI 27.8-28.4). FAS consisted of 58 pts (79% male, median age 68 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage was present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. Resection was performed in 53 pts (91%; 4 refused, 1 unresectable) with R0 resection in 52 pts (98%). 48 (91%) of resected pts started adjuvant Durva and 32 (67%) completed it. Pathological response < ypT2 ypN0 was achieved in 32 pts (18 pts ypT0 and 14 pts ypT1/a/is), corresponding to 60% of resected pts and 55% of the FAS. EFS at 2 yrs was overall 76.1% (one-sided 90% CI (lower bound): 67.6%; 95% CI 62.3% - 85.3%), for ypT1/a/is 92.9% and for ypT0 100%. RFS at 2 yrs after R0 resection (N=52) was 83.5% (95% CI 69.6% - 91.4%) and OS at 2 yrs for the FAS population was 87.3% (95% CI 73.8% - 94.1%). Grade 1, 2, 3, 4 adverse events attributed to Durva during overall treatment were 14%, 35%, 19%, 7%, respectively. Conclusions: The addition of perioperative Durvalumab to the standard of care for pts with resectable MIUC results in a high EFS, RFS and OS at 2 yrs, especially for pts with downstaging to

20 Background: Metastatic castration-sensitive prostate cancer (mCSPC) primarily affects older men (OM). In this post-hoc analysis we investigated the safety and efficacy of abiraterone acetate + prednisone (AAP) in older (≥ 70 years) and younger (< 70 years) patients in PEACE-1. Methods: Men with de novo mCSPC were allocated to standard of care (SOC), SOC + AAP, SOC + radiotherapy (RXT), or SOC + AAP + RXT in this 2x2 design phase 3 trial. SOC was initially androgen deprivation therapy (ADT) alone, then from Oct 2015 onwards, the use of docetaxel (D) was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+ D). Efficacy and safety in OM included in PEACE-1 were analyzed with the same methods used in the overall trial (Lancet 2022; 399: 1695-1707). Results: A total of 741 younger men (YM) (63%) and 431 OM (37%) were randomized. OM presented with more altered PS (ECOG 1-2) (36% vs 26% p=0.0003) and less frequent use of docetaxel (D) as part of SOC (66% vs 51% p

Since 1981 Princess Margaret Hospital has used initial active surveillance (AS) with delayed treatment at relapse as the preferred management for all patients with clinical stage I nonseminomatous germ cell tumors (NSGCT).Our aim was to report our overall AS experience and compare outcomes over different periods using this non-risk-adapted approach.Three hundred and seventy-one patients with stage I NSGCT were managed by AS from 1981 to 2005. For analysis by time period, patients were divided into two cohorts by diagnosis date: initial cohort, 1981-1992 (n=157), and recent cohort, 1993-2005 (n=214).Patients were followed at regular intervals, and treatment was only given for relapse.Recurrence rates, time to relapse, risk factors for recurrence, disease-specific survival, and overall survival were determined.With a median follow-up of 6.3 yr, 104 patients (28%) relapsed: 53 of 157 (33.8%) in the initial group and 51 of 214 (23.8%) in the recent group. Median time to relapse was 7 mo. Lymphovascular invasion (p0.0001) and pure embryonal carcinoma (p=0.02) were independent predictors of recurrence; 125 patients (33.7%) were designated as high risk based on the presence of one or both factors. In the initial cohort, 66 of 157 patients (42.0%) were high risk and 36 of 66 patients (54.5%) relapsed versus 17 of 91 low-risk patients (18.7%) (p0.0001). In the recent cohort, 59 of 214 patients (27.6%) were high risk and 29 of 59 had a recurrence (49.2%) versus 22 of 155 low-risk patients (14.2%) (p0.0001). Three patients (0.8%) died from testis cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one.Non-risk-adapted surveillance is an effective, simple strategy for the management of all stage I NSGCT.

The current standard treatment for early stage (I-III) renal cell cancer (RCC) is surgery. While the prognosis of stage I tumors is excellent, stage II and particularly stage III have a high risk of relapse. The adjuvant treatment of patients with RCC remains an area of investigation, with patient selection being a key aspect. There are currently two prognostic nomograms to establish the risk of relapse in patients with resected RCC. The results of earlier studies of adjuvant therapy, including the use chemotherapy and/or immunotherapy after nephrectomy have failed to show any benefit in the outcome of patients at risk of developing local recurrence or distant metastases. Two recent phase III trials with vaccines (autologous tumor cell vaccine and autologous tumor-derived heat shock protein peptide complex-96) have shown promising, albeit still preliminary, results. In the metastatic RCC setting, recent advances in the molecular understanding of oncogenic pathways have led to the development of new therapeutic strategies with the use of targeted therapies in the adjuvant setting. Neoadjuvant treatment is another treatment modality currently being evaluated for patients with early disease and in patients with metastatic RCC with inoperable primary tumors. The questions that remain unanswered include activity of these agents in early stages of the disease, patient selection, optimal start time of the adjuvant treatment, and finally, the optimal length of treatment.

Advanced and metastatic prostate cancer continues to represent a significant healthcare burden. Since the publication of two randomized trials that showed significant survival and palliative benefits for men treated with docetaxel, this drug has become the treatment of choice for patients with metastatic castration resistant prostate cancer (CRPC).This review discusses the development and current use of docetaxel in metastatic CRPC, as well as future clinical applications.The current literature, meeting abstracts and ClinicalTrials.gov have been reviewed. The most relevant studies involving patients with prostate cancer receiving therapy with docetaxel, alone or in combination with other agents, have been summarised.Docetaxel monotherapy is the approved treatment for patients with metastatic CRPC, and its association with other agents, such as targeted therapies, is currently under study. Several trials are currently ongoing to investigate the use of docetaxel in the early stages of disease, particularly in the neoadjuvant and adjuvant settings for patients with high-risk disease.

Metastatic hormone-resistant prostate cancer has proven largely resistant to cytotoxic therapy. Since 2004, docetaxel (Taxotere)/prednisone has become the standard chemotherapy used to treat advanced hormone-resistant prostate cancer. However, the survival advantage is modest and a significant number of patients do not respond to chemotherapy. It is hoped that an increased understanding of the mechanisms underlying the progression of prostate cancer will lead to new treatment modalities. With the growing number of biologic and targeted agents under development, the potential armamentarium of prostate cancer treatments is steadily growing. However, none of the new treatment modalities has yet been shown to be more effective than standard treatments. This article will provide an overview of targeted or innovative therapies in the treatment of prostate cancer.

A 29-year-old Hispanic male with an unremarkable past medical history, was diagnosed with a mediastinal germ cell tumor (GCT) of mixed histology including choriocarcinoma, embryonal carcinoma and teratomatous components. At the time of diagnosis the human chorionic gonadotropin (HCG) was 287 IU/l [normal range 52], alphafetoprotein (AFP) 421 mgr/l [normal range 55] and LDH 215 IU/l [normal range 5190]. No testicular primary or other metastasic sites were observed. The patient received treatment with a combination of bleomycin, etoposide and cisplatin [BEP] for four cycles achieving a normalization of the tumoral markers but only a mild reduction of the tumor volume. Shortly afterwards due to radiological progression, an R0 resection of the mediastinal mass was performed. Pathologic examination revealed a mixed histology with mature teratoma, gastrointestinal adenocarcinoma and sarcoma components together with extensive areas of fibrosis and necrosis. Two months later, the patient relapsed presenting with multiple pulmonary nodules and one suspicious liver lesion. A hepatic biopsy confirmed the diagnosis of teratoma with malignant transformation in keeping with sarcoma. The patient was then treated with a combination of vinblastine, ifosfamide and cisplatin (VeIP) with no response after two cycles. During treatment course he presented with a painless small nodule on his left inferior eyelid measuring around 8 mm (Figure 1a and b). A biopsy of this nodule (Figure 2) revealed areas of normal conjunctiva (white arrow) along with sarcomatoid components (black arrow) in keeping with metastatic sarcoma. Further systemic treatment options were discussed with the patient who rejected any active approach. To date, four months after diagnosis of this metastasis, the patient remains clinically stable with no symptoms. Though GCTs account for only 1 2% of all human malignancies they are the most common tumors diagnosed in men ages 15 to 34 years [1]. Only 10% of GCTs present as extragonadal malignancies arising in the mediastinum, retroperitoneum and central nervous system in order of frequency. The biology of GCTs is unique having the capacity to display totipotential differentiation ranging from embryonal carcinoma to extraembryonic cell types (i.e. yolk sac tumor or choriocarcinoma) or to somatic cell types (i.e. teratoma) [2]. Teratomas are tumors that display somatic elements with diverse differentiation stages (i.e. mature and immature teratomas). On rare occasions the teratomatous component in a GCT may undergo malignant transformation leading to histology indistinguishable from a somatic malignancy. Examples of histologic transformed cell types include rhabdomyosarcoma