Era Of Immunotherapy Research Articles

Radiomic biomarkers for platinum-refractory head and neck cancer in the era of immunotherapy.

Immune checkpoint inhibitors (ICI) are recommended as the first-line therapy for platinum-refractory head and neck squamous cell carcinoma (HNSCC), a disease with a poor prognosis. However, biomarkers in this situation are rare. The objective was to identify radiomic features-associated biomarkers to guide the prognosis and treatment opinions in the era of ICI. A total of 31 platinum-refractory HNSCC patients were retrospectively enrolled. Of these, 65.5% (20/31) received ICI-based therapy and 35.5% (11/31) did not. Radiomic features of the primary site at the onset of recurrent metastatic (R/M) status were extracted. Prognostic and predictive radiomic biomarkers were analysed. The median overall survival from R/M status (R/M OS) was 9.6 months. Grey-level co-occurrence matrix-associated texture features were the most important in identifying the patients with or without 9-month R/M death. A radiomic risk-stratification model was established and equally separated the patients into high-, intermittent- and lower-risk groups (1-year R/M death rate, 100.0% vs. 70.8% vs. 27.1%, p = 0.001). Short-run high grey-level emphasis (SRHGE) was more suitable than programmed death ligand 1 (PD-L1) expression in selecting whether patients received ICI-based therapy. Radiomic features were effective prognostic and predictive biomarkers. Future studies are warranted.

Achieving precise non-invasive ROS spatiotemporal manipulation for colon cancer immunotherapy

Colon cancer (CC) stands as a formidable global health challenge, ranking as the third leading cause of cancer-related mortality. Traditional photodynamic therapy encounters limitations stemming from the limited penetration depth of light and the effective regulation of reactive oxygen species (ROS). Here, we present an in-situ ROS spatiotemporal manipulation system that synergizes the power of piezoelectric nanoparticles with potent immune adjuvants. This exclusive ROS nanogenerator exhibits precision in targeting colon tumor sites, inducing controlled oxidative stress to eliminate malignant cells, while simultaneously unleashing the full potential of the immune system to suppress cancer cell growth and impede metastasis. Notably, this system achieves spatiotemporal manipulation of ROS through piezocatalytic mechanisms triggered self-generated ROS. Moreover, it skillfully customizes ROS production in response to tumor size, optimizing therapeutic efficacy with precision. To enhance the therapeutic efficacy, glucan, a bioactive polysaccharide that augments the immune response while simultaneously inhibiting the spread of cancer cells, is integrated. This cancer treatment approach is enabling precise ROS generation and immune modulation at the tumor site, ushering in a new era of dynamic immunotherapy.

In era of immunotherapy: the value of trastuzumab beyond progression in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer.

For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial. The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy. Retrospective analysis. Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan-Meier method and compared using the log-rank test. In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8-8.2] and 3.5 (95% CI = 2.2-4.8) months, respectively (p = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3-4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%. The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy. This study is a retrospective study, which does not require clinical registration.

The antitumor effect of diisopropylamine dichloroacetate on non-small cell lung cancer and its influence on the tumor immune microenvironment.

To evaluate the antitumor effects of diisopropylamine dichloroacetate (DADA) alone or in combination with chemotherapy/radiotherapy/immunotherapy in NSCLC and explore the underlying mechanisms involved. MTT, UV spectrophotometry, flow cytometry, fluorescence microscopy, and clonogenic survival assays were used. In LLC mouse models, the antitumor effects of radiotherapy, DADA, and the anti-PD-1 antibody alone or in combination were evaluated, and the T cell numbers were evaluated in different groups. DADA significantly inhibited lactate production and promoted apoptosis in NSCLC in vitro. Compared with pemetrexed or DADA alone, the combination of DADA with pemetrexed significantly inhibited proliferation and promoted apoptosis (p<0.05). This may be related to the decrease in the mitochondrial membrane potential in the combined group. Moreover, compared with radiotherapy alone, the combination of DADA with radiotherapy induced remarkable DNA damage. In vivo, the combination of radiotherapy, an anti-PD-1 antibody and DADA resulted in superior tumor inhibition than the combination of radiotherapy and anti-PD-1 antibody did (p < 0.05). The underlying mechanism may be partially related to the increased number of CD3+ T cells in the triplet combination group (p < 0.05). Our results showed that DADA has strong antitumor effects on NSCLC, either alone or in combination with chemotherapy or radiotherapy. Interestingly, the combination of radiotherapy, anti-PD-1 antibody and DADA had a more pronounced tumor-suppressing effect, which may be related to DADA-induced T-cell generation by reducing local lactic acid production in the tumor microenvironment. This study lays the foundation for further exploration of DADA in lung cancer, especially in the era of immunotherapy, on the basis of its possible immunomodulatory effects.

Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment.

Immune checkpoint inhibitors (ICIs) have heralded a new era in immunotherapy, representing a pivotal breakthrough in cancer treatment. Their impact is profound, with ICIs standing as some of the most prescribed anticancer therapies today. Notably, their ability to induce long-term remission even after treatment cessation provides genuine hope for achieving durable cures. However, despite these strides, challenges persist in the landscape of oncology, including resistance phenomena, immune-related adverse events, and suboptimal response rates. In response to these challenges, combination therapy emerges as a promising approach, poised to enhance treatment outcomes and address limitations inherent to single-agent ICI therapy. By synergistically targeting multiple pathways, combination therapy holds the potential to augment therapeutic efficacy while mitigating toxicity and impeding the emergence of resistance mechanisms. Understanding the intricacies underlying resistance development and adverse events is paramount in devising novel and refined combination strategies. A timeline showing FDA approvals of ICIs combination is shown in Figure 1. This review aims to provide a comprehensive and up-to-date examples of different combined therapy strategies that can be used to overcome various challenges regarding ICI treatment. Through the exploration of innovative therapeutic combinations, we aim to provide clinicians and researchers with actionable knowledge to optimize patient outcomes and propel the field of immuno-oncology forward.

Challenges and opportunities in the immunotherapy era: balancing expectations with hope in small-cell lung cancer.

Small-cell lung cancer (SCLC) is a biologically aggressive subtype of lung cancer, a lethal disease characterized by rapid tumor growth, early relapse, a strong tendency for early widespread metastasis, and high genomic instability, making it a formidable foe in modern oncology practice. While the management of non-SCLC has been revolutionized in the era of immunotherapy, progress in SCLC has been more muted. Recent randomized phase III clinical trials have combined programmed death ligand-1 inhibitors to a chemotherapy backbone and demonstrated improved survival; however, the absolute benefit observed is short months. There is an undeniable urgent need for better responses, better agents, novel therapeutic approaches, and more rational, biomarker-driven clinical trials in SCLC. In this review, we discuss the rationale and current understanding of the biology of SCLC in the modern era of immunotherapy, discuss recent advances in front-line immunotherapeutic approaches that have changed clinical practice globally, provide an overview of some of the challenges and limitations that have staggered immune checkpoint blockade in SCLC, and explore some of the novel immunotherapeutic approaches currently being investigated.

Camrelizumab combined with apatinib and nanoparticle albumin-bound paclitaxel in lung adenocarcinoma (CAPAP-lung): a single-arm phase II study

Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200mg intravenously, day one), apatinib (250mg, q.d., five continuous days per week), and nab-paclitaxel (135mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle14. Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

An Overview of the Bench to Bedside Models of Breast Cancer in the Era of Cancer Immunotherapy

Lymphoma involves abnormal lymphoid cell growth, often originating in lymphatic tissue, but in this case series non-Hodking's lymphoma is visible in the extra-nodal region. This research explores different lymphoma cases, focusing on diverse presentations and utilizing modern imaging for evaluation. Four cases are detailed, involving an 18-year-old woman with tonsillar lymphoma, a 69-year-old man with ocular lymphoma, a 38-year-old lady with abdominal lymphoma, and a 30-year-old man with gastric lymphoma. All cases received adjuvant chemotherapy (RCHOP), leading to significant symptom relief after four cycles. One of the barriers to novel treatment developments within breast cancer is the ability to prove efficacy in the preclinical setting before moving on to clinical trials. Preclinical models range from single cell monolayers to more sophisticated humanised PDXs systems each with their set of advantages and limitations. Modelling the immune environment in cold tumours, such as breast cancer can also be challenging as are currently no clearly defined markers that can stratify patients based on treatment response. Immune checkpoints receptors such as PD-L1 may not show predictive outcomes in this tumour type. Furthermore, the heterogeneity of breast cancer may be difficult to recapitulate at the bench side. In this review, we provide an overview of the available in vitro, in vivo and ex vivo models of breast cancer with consideration of how these may extrapolated to the investigation of the role of the immune system and immunotherapy developments in breast cancer.

Strategies and perspectives for addressing immune checkpoint inhibitor resistance in the era of combination immunotherapy for advanced hepatocellular carcinoma

Strategies and perspectives for addressing immune checkpoint inhibitor resistance in the era of combination immunotherapy for advanced hepatocellular carcinoma

Exploring potential predictive biomarkers through historical perspectives on the evolution of systemic therapies into the emergence of neoadjuvant therapy for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a type of liver cancer, ranks as the sixth most prevalent cancer globally and represents the third leading cause of cancer-related deaths. Approximately half of HCC patients miss the opportunity for curative treatment and are then limited to undergoing systemic therapies. Currently, systemic therapy has entered the era of immunotherapy, particularly with the advent of immune-checkpoint inhibitors (ICIs), which have significantly enhanced outcomes for patients with advanced HCC. Neoadjuvant treatment for HCC has become a possibility-findings from the IMbrave 050 trial indicated that ICIs offer the benefit of recurrence-free survival for high-risk HCC patients post-resection or local ablation. However, only a small fraction of individuals benefit from systemic therapy. Consequently, there is an urgent need to identify predictive biomarkers for treatment response and outcome assessment. This study reviewed the historical progression of systemic therapy for HCC, highlighting notable therapeutic advancements. This study examined the development of systemic therapies involving conventional drugs and clinical trials utilized in HCC treatment, as well as potential predictive biomarkers for advanced and/or locally advanced HCC. Various studies have revealed potential biomarkers in the context of HCC treatment. These include the association of dendritic cells (DCs) with a favorable response to neoadjuvant therapy, the presence of enriched T effector cells and tertiary lymphoid structures, the identification of CD138+ plasma cells, and distinct spatial arrangements of B cells in close proximity to T cells among responders with locally advanced HCC receiving neoadjuvant cabozantinib and nivolumab treatment. Furthermore, pathological response has been associated with intratumoral cellular triads consisting of progenitor CD8+ T cells and CXCL13+ CD4+ T helper cells surrounding mature DCs in patients receiving neoadjuvant cemiplimab for resectable HCC. Despite no widely recognized predictive biomarkers for HCC individualized treatment, we believe neoadjuvant trials hold the most promise in identifying and validating them. This is because they can collect multiple samples from resectable HCC patients across stages, especially with multi-omics, bridging preclinical and clinical gaps.

The role of dacarbazine and temozolomide therapy after treatment with immune checkpoint inhibitors in malignant melanoma patients: A case series and meta-analysis.

Dacarbazine (DTIC) and its oral counterpart temozolomide (TMZ) have been the most used agents in advanced malignant melanoma (MM) patients and they are still used routinely. The preferred first line treatment, immune checkpoint inhibitors (CPIs) might shape the tumor and the tumor microenvironment, possibly affecting the response to subsequent therapies. The aim of this study was to investigate the treatment effect of DTIC/TMZ in MM patients after CPI therapy in a consecutive patient cohort and through systematic literature review and meta-analysis. Thirty-five patients with advanced MM treated with DTIC/TMZ after previous CPI therapy in three Swedish regions between 2017 and 2021 were recognized and seven case series studies were identified through systematic database review. Pooled data from all 345 patients showed a median real-world progression-free survival (rwPFS) of 1.9 months and overall survival (OS) of 6.0 months. Three of these studies were included in a meta-analysis comparing DTIC/TMZ after CPI treatment, versus no previous immunotherapy, showing no statistically significant differences in rwPFS or OS but higher real-world response rate to chemotherapy for the prior-CPI treated group (Odds Ratio: 2.24; 95% Confidence Interval: 1.04-4.86). The current study supports consideration of DTIC/TMZ in later line of treatment in the immunotherapy era.

Recombinant humanized Fab fragments targeting the CFC domain of human Cripto-1

In the era of immunotherapy, the targeting of disease-specific biomarkers goes hand in hand with the development of highly selective antibody-based reagents having optimal pharmacological/toxicological profiles. One interesting and debated biomaker for several types of cancers is the onco-fetal protein Cripto-1 that is selectively expressed in many solid tumours and has been actively investigated as potential theranostic target. Starting from previously described anti-CFC/Cripto-1 murine monoclonal antibodies, we have moved forward to prepare the humanized recombinant Fabs which have been engineered so as to bear an MTGase site useful for a one-step site-specific labelling. The purified and bioconjugated molecules have been extensively characterized and tested on Cripto-1-positive cancer cells through in vitro binding assays. These recombinant Fab fragments recognize the target antigen in its native form on intact cells suggesting that they can be further developed as reagents for detecting Cripto-1 in theranostic settings.

Neutrophil-to-Lymphocyte Ratio (NLR) in NSCLC, Gastrointestinal, and Other Solid Tumors: Immunotherapy and Beyond.

In the era of immunotherapy, identifying biomarkers of immune system activation has become a high-priority challenge. The blood neutrophil-to-lymphocyte ratio (NLR) has been largely investigated as a biomarker in several cancer types. NLR values have been shown to mirror the tumor-induced inflammatory status and have been demonstrated to be a reliable prognostic tool across stages of disease and therapeutic approaches. When integrated with other biomarkers of response to immunotherapy, such as PD-L1, tumor mutational burden, and tumor-associated immune cells, the NLR may allow to further stratify patients with different likelihoods of deriving a significant clinical benefit. However, despite its accessibility, low cost, and easy interpretation, the NLR is still poorly used as a prognostic tool in daily clinical practice. In this review, we analyze the role of the NLR in defining the relationship between cancer and the immune system, its usefulness in daily clinical practice, and its relationship with other established or emerging biomarkers of immunotherapy outcomes.

The Era of Immunotherapy in Small-Cell Lung Cancer: More Shadows Than Light?

Small-cell lung cancer is an extremely chemo-sensitive disease; the addition of immunotherapy to chemotherapy has demonstrated a slight clinical benefit in pivotal trials, even with a statistically significant difference in terms of survival outcomes when compared to chemotherapy alone. In this scenario, the role of radiotherapy as a consolidation treatment in thoracic disease or as a prophylactic therapy in the brain should be clarified. In addition, due to the frailty and the poor prognostic characteristics of these patients, the need for predictive biomarkers that could support the use of immunotherapy is crucial. PD-L1 and TMB are not actually considered definitive biomarkers due to the heterogeneity of results in the literature. A new molecular classification of small-cell lung cancer based on the expression of key transcription factors seems to clarify the disease behavior, but the knowledge of this molecular subtype is still insufficient and the application in clinical practice far from reality; this classification could lead to a better understanding of SCLC disease and could provide the right direction for more personalized treatment. The aim of this review is to investigate the current knowledge in this field, evaluating whether there are predictive biomarkers and clinical patient characteristics that could help us to identify those patients who are more likely to respond to immunotherapy.

Current status of vaccine immunotherapy for gastrointestinal cancers.

Recent advances in tumor immunology and molecular drug development have ushered in a new era of cancer immunotherapy. Immunotherapy has shown promising results for several types of tumors, such as advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin's lymphoma. Similarly, efforts have been made to develop immunotherapies such as adoptive T-cell transplantation, peptide vaccines, and dendritic cell vaccines, specifically for gastrointestinal tumors. However, before the advent of immune checkpoint inhibitors, immunotherapy did not work as well as expected. In this article, we review immunotherapy, focusing on cancer vaccines for gastrointestinal tumors, which generally target eliciting tumor-specific CD8 + cytotoxic T lymphocytes (CTLs). We also review various vaccine therapies and describe the relationship between vaccines and adjuvants. Finally, we discuss prospects for the combination of immunotherapy with immune checkpoint inhibitors.

Clinicopathological Study of PD-1/PD-L1 Expression in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with Emphasis on Large B-Cell Richter Transformation.

In the era of immunotherapy, inhibition of the PD-1/PD-L1 immune checkpoint pathway has changed the therapeutic landscape for many tumors. Limited studies were performed on the expression of PD-1 in chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL) and its Richter transformation into diffuse large B-cell lymphoma (DLBCL-RT). This study aims to evaluate PD-1/PD-L1 expression and their prognostic role in CLL/SLL, DLBCL-RT, and DLBCL-de novo patients. This retrospective study was conducted on 96 cases (38 CLL/SLL, 11 DLBCL-RT and 47 DLBCL-de novo) that were retrieved from the pathologic and clinical databases at the Oncology Center, Mansoura University. Immunohistochemical evaluation of PD-1 and PD-L1 was assessed in tumor cells and the microenvironment in those patients. This study demonstrated positive expression of PD-1 in CLL/SLL patients, mainly in proliferation centers. Moreover, it showed a higher prevalence of PD-1 expression in DLBCL-RT (9/11 patients) than in DLBCL-de novo (5/47 patients) (P < 0.001). Tumor cells revealed positive PD-L1 expression in 5/47 DLBCL-de novo patients and negative PD-L1 expression in all CLL/SLL and DLBCL-RT patients. PD-1 was positive in reactive T-cells, and PD-L1 was positive in background histiocytes and dendritic cells in all studied cases. PD-1 positive expression in tumor cells was considered an independent poor prognostic factor for overall survival (OS) in DLBCL patients (P = 0.04). In addition, DLBCL-RT had a significantly shorter OS than DLBCL-de novo (P = 0.005). The high prevalence of PD-1 expression in DLBCL-RT patients supports the promising and potential role of anti-PD-1 immunotherapy in the treatment of DLBCL-RT patients.

Treatment Patterns and Real-World Outcomes for Locally Advanced or Metastatic Urothelial Cancer in the Era of Immunotherapy

Background and objectiveThere are limited data on real-world outcomes for patients with advanced or metastatic urothelial cancer (mUC) since immune checkpoint inhibitors (ICIs) became available. Our objective was to analyze outcomes for patients with mUC since ICIs became available. MethodsWe performed a retrospective analysis of 131 patients with mUC attending the outpatient clinic of a single tertiary care center who received systemic therapy between June 2017 and July 2021 with follow-up up to December 2022. Summary and descriptive statistics were calculated for categorical and continuous variables. The Kaplan-Meier method was applied to calculate survival, and a Cox proportional-hazards model was used to explore associations between clinical variables and outcomes. Key findings and limitationsThe median patient age was 68 yr (range 35–90). The first systemic therapy administered was platinum-based in 79% of cases and ICI-based in 21%. Some 61% of the cohort received a second systemic treatment, with 75% of these an ICI. Median overall survival for the entire cohort was 24 mo (interquartile range 9–35). Patients on ICI therapy for ≥6 mo had median overall survival of 59 mo (95% confidence interval 39 mo–not reached). Metastatic sites on initiation of ICI therapy and C-reactive protein kinetics were prognostic in patients receiving ICIs. Limitations include the retrospective design and inherent selection bias. Conclusions and clinical implicationsMore than 60% of patients with mUC received second-line treatment, and 75% of these received an ICI. Patients staying on immunotherapy for more than 6 mo have substantially better outcomes in comparison to patients with less time on immunotherapy and historical cohorts. Patient summaryWe looked at the lines of therapy and outcomes for patients with advanced or metastatic cancer of the urinary tract, starting from when immunotherapy drugs called immune checkpoint inhibitors (ICIs) became available. We found that 60% of patients have received second-line therapy, which is a double the rate in comparison to historical groups of patients. Patients with long-term ICI therapy (>6 months) had significantly better outcomes, with a median survival of more than 3 years.

Dosimetric predictors of radiation pneumonitis in patients with prior immunotherapy exposure: A multi-institutional analysis

Background and purposeCombining immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) may magnify the radiation pneumonitis (RP) risk. Dosimetric parameters can predict RP, but dosimetric data in context of immunotherapy are very scarce. To address this knowledge gap, we performed a large multicenter investigation to identify dosimetric predictors of RP in this under-studied population. Materials and methodsAll lung cancer patients from five institutions who underwent conventionally-fractionated thoracic intensity-modulated radiotherapy with prior ICI receipt were retrospectively compiled. RP was defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. ResultsThe vast majority of the 192 patients (median follow-up 14.7 months) had non-small cell lung cancer, received PD-1 inhibitors, and did not receive concurrent systemic therapy with TRT. Grades 1–5 RP occurred in 21.9%, 25.0%, 8.3%, 1.6%, and 1.0%, respectively. The mean MLD for patients with grades 1–5 RP was 10.7, 11.6, 12.6, 14.7, and 12.8 Gy, respectively. On multivariable analysis, tumor location and mean lung dose (MLD) significantly predicted for any-grade and grade ≥ 2 pneumonitis. Only MLD significantly predicted for grade ≥ 3 RP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD thresholds, which can be an assistive tool during TRT treatment planning. ConclusionThis study, by far the largest to date of dosimetric predictors of RP in the immunotherapy era, illustrates that MLD is the most critical dose-volume parameter influencing RP risk. These data may provide a basis for revising lung dose constraints in efforts to better prevent RP in this rapidly expanding ICI/TRT population.

The Role of Thoracic Vertebral Body Dosimetry in Minimizing Acute Hematologic Toxicities of Patients With Non-Small Cell Lung Cancer Receiving Lung Radiation Therapy and Immunotherapy

IntroductionHematologic toxicities (HTs) are among the most common toxicities of combined immunotherapy and radiotherapy (RT). It remains essential to prevent RT-induced HTs because they can cause treatment discontinuation (influencing antitumoral effects), and because lymphopenia might dampen the effects of immunotherapy. To date, there are no studies examining the impact of thoracic vertebral body (TVB) RT dose on HTs in non-small cell lung cancer (NSCLC) patients receiving combined lung RT and PD(L)-1 immunotherapy. MethodsFor standardization, all doses were reported as 2-Gy equivalents (EQD2). Mirroring publications prior to the immunotherapy era, TVB volumes referred to T1-T10 and specific dosimetric parameters (DmeanEQD2, V5EQD2‒V60EQD2) were analyzed. Logistic regression estimated associations between grade ≥3 HTs (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability (NTCP) models were constructed by logistic regression analysis modeling for HT3+. Receiver operating characteristic (ROC) analysis delineated TVB dosimetric thresholds, stratification of which was able to evaluate post-RT absolute lymphocyte count (ALC) and immunotherapy responses. Areas under the curve (AUCs) for NTCP models were corroborated by bootstrapping (optimism-corrected) methodology. ResultsIn 132 patients, there were 26 (19.7%) instances of HT3+. On multivariate analysis, DmeanEQD2 and V5EQD2‒V20EQD2 associated with HT3+ (P<0.05 for all). The NTCP models illustrated a 50% probability of HT3+ at a DmeanEQD2=39.8 Gy, V5EQD2=87.4%, V10EQD2=77.0%, and V20EQD2=68.4%. ROC analysis delineated optimal thresholds of HT3+ with DmeanEQD2 ±30.2 Gy, V5EQD2 ±69.1%, V10EQD2 ±64.6%, and V20EQD2 ±53.5%. Patients treated with values above those cutoffs had over double the risk of HT3+, with significant differences in post-RT ALC and immunotherapy responses (P<0.05 for all). AUCs for each individual parameter ranged from 0.743 to 0.798, and combining all four aforementioned cutoffs into a ROC curve resulted in a qualitatively higher AUC (0.836). ConclusionsThis hypothesis-generating work suggests that TVB dosimetry may equate with HT3+ in NSCLC patients undergoing combined lung RT/immunotherapy. Applying TVB dose constraints in this population could reduce HT3+ and avoid dampening of immunotherapy responses, but prospective validation is required.

Cancer Vaccines in the Immunotherapy Era: Promise and Potential.

Therapeutic vaccines are a promising alternative for active immunotherapy for different types of cancers. Therapeutic cancer vaccines aim to prevent immune system responses that are not targeted at the tumors only, but also boost the anti-tumor immunity and promote regression or eradication of the malignancy without, or with minimal, adverse events. Clinical trial data have pushed the development of cancer vaccines forward, and the US Food and Drug Administration authorized the first therapeutic cancer vaccine. In the present review, we discuss the various types of cancer vaccines and different approaches for the development of therapeutic cancer vaccines, along with the current state of knowledge and future prospects. We also discuss how tumor-induced immune suppression limits the effectiveness of therapeutic vaccinations, and strategies to overcome this barrier to design efficacious, long-lasting anti-tumor immune responses in the generation of vaccines.