The combination of radiation and immunotherapy is currently an exciting avenue of pre-clinical and clinical investigation. The synergy between these two treatment modalities has the potential to ...expand the role of radiation from a purely local therapy, to a role in advanced and metastatic disease. Tumor regression outside of the irradiated field, known as the abscopal effect, is a recognized phenomenon mediated by lymphocytes and enhanced by checkpoint blockade. In this review, we summarize the known mechanistic data behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy. We also provide pre-clinical data supporting specific radiation timing and optimal dose/fractionation for induction of a robust anti-tumor immune response with or without checkpoint blockade. Importantly, these data are placed in a larger context of understanding T-cell exhaustion and the impact of immunotherapy on this phenotype. We also include relevant pre-clinical studies done in non-tumor systems. We discuss the published clinical trials and briefly summarize salient case reports evaluating the abscopal effect. Much of the data discussed here remains at the preliminary stage, and a number of interesting avenues of research remain under investigation.
Recent discoveries in cancer biology have greatly increased our understanding of cancer at the molecular and cellular level, but translating this knowledge into safe and effective therapies for ...cancer patients has proved to be challenging. There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost. Biomarkers are central to accelerating the identification and adoption of new therapies, but currently, many barriers impede their use in drug development and clinical practice. In 2007, the AACR-FDA-NCI Cancer Biomarkers Collaborative stepped into the national effort to bring together disparate stakeholders to clearly delineate these barriers, to develop recommendations for integrating biomarkers into the cancer drug development enterprise, and to set in motion the necessary action plans and collaborations to see the promise of biomarkers come to fruition, efficiently delivering quality cancer care to patients.
As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new ...therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy. Such interrogation of the tumor, blood, and host immune parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. To approach these opportunities for progress, the Society for Immunotherapy of Cancer (SITC) reconvened the Immune Biomarkers Task Force. Comprised of an international multidisciplinary panel of experts, Working Group 4 sought to make recommendations that focus on the complexity of the tumor microenvironment, with its diversity of immune genes, proteins, cells, and pathways naturally present at baseline and in circulation, and novel tools to aid in such broad analyses.
Regenerative stem cell-like memory (T
) CD8
T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T
that have naive phenotype with ...self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T
cells exhibited plasticity and loci-specific profiles similar to bona fide T
isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8
T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8
T cell reprogramming into T
that acts as a reservoir for effector T cells with potent therapeutic characteristics.
Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be ...applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered.
We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-escalation design.
The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose.
Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development.
To modulate T-cell function for cancer therapy, one challenge is to selectively attenuate regulatory but not conventional CD4
T-cell subsets regulatory T cell (Treg) and conventional T cell (Tconv). ...In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4
T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv. Conversely, PI3Kδ was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T cells within the tumor microenvironment, eliciting potent antitumor efficacy. Overall, our results offer a mechanistic rationale to employ PI3Kδ inhibitors to selectively target Treg and improve cancer immunotherapy.
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Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule ...inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models.
This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed.
Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (T
~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t
~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease.
Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed.
ClinicalTrials.gov identifier: NCT02048709 .
The 2022 Immunotherapy Bridge congress (November 30-December 1, Naples, Italy) featured a Great Debate session which addressed three contemporary topics in the field of immunotherapy. The debates ...included counterpoint views from leading experts and considered whether adoptive cell therapy (ACT) has a role in the treatment of solid tumors, the use of peripheral/blood biomarkers versus tumor microenvironment biomarkers for cancer immunotherapy and the role of chimeric antigen receptor T cell versus natural killer cell therapy. As is the tradition in the Immunotherapy Bridge Great Debates, speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect their own personal views. Audiences voted in favour of either side of the topic both before and after each debate.
Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor ...microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher "immunogenic potential". This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.
Durvalumab selectively blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1. Encouraging clinical activity and manageable safety were reported in urothelial carcinoma, ...non–small-cell lung cancer (NSCLC), hepatocellular carcinoma (HC) and small-cell lung cancer (SCLC) in a multicenter phase I/II study. Safety and clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) were evaluated in the expansion phase.
Patients received 10 mg/kg of durvalumab intravenously every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. The primary objective was safety; clinical activity was a secondary objective.
Sixty-two patients were enrolled and evaluable (received first dose ≥24 weeks before data cutoff). Median age was 57 years; 40.3% were human papillomavirus (HPV)-positive; 32.3% had tumour cell PD-L1 expression ≥25%, and 62.9% were current/former smokers. They had a median of 2 prior systemic treatments (range, 1–13). All-causality adverse events (AEs) occurred in 98.4%; drug-related AEs occurred in 59.7% and were grade III–IV in 9.7%. There were no drug-related discontinuations or deaths. Objective response rate (blinded independent central review) was 6.5% (15.0% for PD-L1 ≥25%, 2.6% for <25%). Median time to response was 2.7 months (range, 1.2–5.5); median duration was 12.4 months (range, 3.5–20.5+). Median progression-free survival was 1.4 months; median overall survival (OS) was 8.4 months. OS rate was 62% at 6 months and 38% at 12 months (42% for PD-L1 ≥25%, 36% for <25%).
Durvalumab safety in HNSCC was manageable and consistent with other cohorts of the study. Early, durable responses in these heavily pretreated patients warrant further investigation; phase III monotherapy and combination therapy studies are ongoing.
clinicaltrials.gov NCT01693562; MedImmune study 1108.
•Durvalumab monotherapy was safe in previously treated recurrent/metastatic head and neck squamous cell carcinoma.•Durable antitumour responses were observed, similar to other tumour cohorts.•Objective response rate and disease control rate were greater in patients with ≥25% vs <25% tumoural PD-L1 expression.
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