Vaccine strategies to improve anti-cancer cellular immune responses

More than many other fields in medicine, cancer vaccine development has been plagued by a wide gap between the massive amounts of highly encouraging preclinical data on one hand, and the disappointing clinical results on the other. It is clear now that traditional approaches from the infectious diseases' vaccine field cannot be borrowed as such to treat cancer. This review highlights some of the strategies developed to improve vaccine formulations for oncology, including research into more powerful or "smarter" adjuvants to elicit anti-tumoral cellular immune responses. As an illustration of the difficulties in translating smart preclinical strategies into real benefit for the cancer patient, the difficult road of vaccine development in lung cancer is given as example. Finally, an outline is provided of the combinatorial strategies that leverage the increasing knowledge on tumor-associated immune suppressive networks. Indeed, combining with drugs that target the dominant immunosuppressive pathway in a given tumor promises to unlock the true power of cancer vaccines and potentially offer long-term protection from disease relapse

Adjuvant Therapy for Renal Cell Carcinoma: Hype or Hope?

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration’s approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions

Improving Outcomes for Patients with Higher Risk Locally Advanced Renal Cancer

Background: Renal Cell Carcinomas (RCCs) are a heterogeneous group of malignancies. Although patients presenting with locally advanced tumours may be cured by surgery alone, many subsequently relapse and succumb to their disease. Studies of adjuvant tyrosine-kinase-inhibitors (TKIs) did not meet their primary goals but provide a rich data source to refine prognostication in contemporary patients and inform the design of clinical trials testing new therapeutic approaches. Methods: This study included patients treated surgically with curative intention from two international clinical trials testing the addition of TKIs in intermediate and high-risk patients; SORCE (n=1711) and ASSURE (n=1943). Three questions were addressed; A validation of the 2003 Leibovich prognostic score (a widely used scoring system) in contemporary patients with clear-cell and non-clear-cell RCCs, also comparing this with the Tumour/Nodes/Metastases (TNM) classification. Discrimination and calibration were assessed by comparing data from SORCE to original data used to derive the Leibovich score using Harrell’s concordance-indexes, Kaplan-Meier curves and hazard ratios (HRs). Secondly data from SORCE and ASSURE were combined, generating a large dataset to examine clinical characteristics of higher risk non-clear-cell RCC variants (papillary RCC (pRCC), chromophobe RCC (chRCC) and sarcomatoid RCC (sRCC)). The impact of histology on disease-free-survival and overall survival were presented using Kaplan-Meier curves and adjusted Cox regression models. Finally, a retrospective cohort study examining data from SORCE compared outcomes of those relapsing first at single anatomical sites to those relapsing at multiple sites using Kaplan-Meier methodology. The prognostic impact of organ site and time-to-relapse (TTR), performance status and treatments upon relapse were evaluated using Cox regression models. Results: The 2003 Leibovich score demonstrated discriminative accuracy in patients with clear-cell (c-index 0.63, 95% CI 0.61 to 0.65) and non–clear-cell RCCs (c-index 0.64, 95% CI 0.59 to 0.69). Discrimination by the 2003 Leibovich score exceeded that of 2002 TNM (c-indexes of 0.67 (SE 0.01) vs 0.56 (SE 0.01)). Distinct patterns of relapse for patients with chRCC, pRCC and sRCCs were shown. Notably, the median TTR for patients with pRCC was five months less than patients with ccRCC; (1.34 years (IQR 0.76, 2.59) vs 1.78 years (IQR 0.96, 3.38, p=0.012)). Those with pRCC relapsing in the abdomen had almost double the risk of death (HR 1.7 (95% CI 1.15-2.5 p 36 months, respectively (p < 0.003). Conclusion: The 2003 Leibovich score discriminates between intermediate and high-risk patients in multi-subtype RCC populations. Outcomes for patients with non-clear-cell RCCs are heterogeneous; those with pRCC with intra-abdominal first relapses had particularly poor survival. Prognostic groups were defined for patients relapsing after nephrectomy based on number of anatomical sites involved and TTR. These results guide prognostication, future translational work and clinical trial designs for patients presenting with locally advanced RCC