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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

Adoptive cell therapy (ACT) usingex vivoexpanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+TIL-myeloid cell networks

BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.MethodsPhase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.ResultsEighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1–9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs.ConclusionNo safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.Trial registration numberNCT02923349.

Despite COVID-19 pandemic, which is still deeply affecting world economy and global health, medical oncology specialists keep pursuing their effort for the identification of new therapeutic options to improve patients' life expectancy and quality of life. 2021 confirms the immunotherapy efficacy, alone or in combination with other modalities, across several indications. This year, we are summarizing the new approaches in the following sectors: lung, breast, melanoma, gynecological, digestive, urological and ENT areas.En dépit de la pandémie de Covid-19 qui continue à grandement impacter l’économie mondiale et la santé, l’oncologie médicale poursuit sa quête d’identification de nouvelles options thérapeutiques ayant pour buts la prolongation de l’espérance de vie et l’amélioration de la qualité de vie de ses patients, en nombre croissant. L’année 2021 confirme également l’efficacité de l’immunothérapie, seule ou en combinaison à d’autres modalités, dans de nombreuses indications. Cette année, nous vous résumons les nouvelles approches dans les domaines suivants: poumon, sein, mélanome, sphères gynécologique, digestive, urologique et ORL.

The University Hospital of Lausanne has heavily invested in the development of interdisciplinary oncology centers to improve the quality of care, and structure research and training. By integrating specialist nurses, it follows international recommendations. These specialists' nurses rephrase the information given by the doctor and ensure patients' understanding. They assess the patient's psychosocial situation and provides guidance if necessary. They support the patient in making informed choices about treatment and coping strategies. In addition to the outpatient clinics planned in accordance with the care pathway, she can be contacted between appointments to answer questions or concerns of any kind. This article shows the added value of these nurses in the care of oncology patients.

The University Hospital of Lausanne has heavily invested in the development of interdisciplinary oncology centers to improve the quality of care, and structure research and training. By integrating specialist nurses, it follows international recommendations. These specialists' nurses rephrase the information given by the doctor and ensure patients' understanding. They assess the patient's psychosocial situation and provides guidance if necessary. They support the patient in making informed choices about treatment and coping strategies. In addition to the outpatient clinics planned in accordance with the care pathway, she can be contacted between appointments to answer questions or concerns of any kind. This article shows the added value of these nurses in the care of oncology patients.Le CHUV s’est fortement investi dans le développement de centres interdisciplinaires en oncologie afin d’améliorer la qualité de la prise en charge, de structurer la recherche et la formation. En y intégrant des infirmières cliniciennes, il suit les recommandations internationales. Ces infirmières reprennent les informations données par le médecin et s’assurent de la compréhension du patient. Elles évaluent sa situation psychosociale et l’orientent au besoin. Elles soutiennent le patient dans ses choix de traitement ainsi que dans ses stratégies d’adaptation. Outre les entretiens planifiés en fonction du parcours de soins, elles sont joignables entre les rendez-vous pour répondre à des questions ou préoccupations de tout ordre. Cet article montre la plus-value que la présence de ces infirmières offre à la prise en charge des patients oncologiques.

BACKGROUND The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response. OBJECTIVE The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations. METHODS The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. RESULTS The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022. CONCLUSIONS The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients’ needs and to consider their concerns about their PKI self-management, considering the patient as an active partner. CLINICALTRIAL ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/30090

Intravesical immunotherapy with Calmette-Guerin bacillus (BCG) have been used since decades for the treatment of non-muscle invasive bladder cancer and is a proof of principle that immunotherapy works for this malignancy. Since 2016, immune checkpoint inhibitors (ICI) demonstrated clinical benefits in locally advanced or metastatic bladder cancer, providing potentially durable tumor control in first line therapy or upon relapse after standard treatments. Ongoing clinical trials aim to demonstrate the efficiency of ICI for the treatment of localized disease.

Intravesical immunotherapy with Calmette-Guerin bacillus (BCG) have been used since decades for the treatment of non-muscle invasive bladder cancer and is a proof of principle that immunotherapy works for this malignancy. Since 2016, immune checkpoint inhibitors (ICI) demonstrated clinical benefits in locally advanced or metastatic bladder cancer, providing potentially durable tumor control in first line therapy or upon relapse after standard treatments. Ongoing clinical trials aim to demonstrate the efficiency of ICI for the treatment of localized disease.L’immunothérapie par instillation de bacille de Calmette-Guérin est utilisée depuis plusieurs décennies dans le cancer de la vessie non musculo-invasif. Cette forme d’immunothérapie locale est témoin de l’efficacité de cette approche thérapeutique. Depuis 2016, les inhibiteurs de points de contrôle immunitaire (IPCI) complètent l’arsenal thérapeutique notamment lors d’une maladie localement avancée ou métastatique. Ils permettent d’obtenir des résultats bénéfiques potentiellement durables en première ligne de traitement et après échec des traitements standards. Des efforts sont en cours afin de démontrer le bénéfice des IPCI dans la prise en charge de la maladie localisée.

Purpose: This phase 1/2 trial evaluates the novel immunotherapy BMS-986253 in combination with immune checkpoint inhibitors (NCT03400332). Interleukin-8 (IL-8) is an immunosuppressive chemokine often elevated in the serum of patients with cancer. High serum IL-8 concentration is associated with poor prognoses and resistance to immunotherapies, including anti-programmed death-1 (PD-1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents (Schalper et al. Nat Med 2020;26:688). The addition of anti-IL-8 therapy to anti-PD-1 nivolumab (NIVO) and anti-CTLA-4 ipilimumab (IPI) may sensitize patients with high serum IL-8 levels to immune checkpoint inhibition. BMS-986253, a fully human IgG1 anti-IL-8 monoclonal antibody, in combination with NIVO ± IPI is under investigation in a phase 1/2 trial of patients with advanced solid tumors. Initial results from part 1 indicate BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities (Davar et al. J Immunother Cancer 2020;8. Abstract 394). Preliminary antitumor activity was observed, including partial responses in 5 of 28 patients with melanoma that had progressed on or after prior anti-PD-(L)1 therapy, a population with high unmet medical need. Part 2 is a randomized, double-blind phase 2 study comparing the efficacy of BMS-986253 in combination with NIVO + IPI vs NIVO + IPI in patients with advanced melanoma that progressed on or after prior anti-PD-(L)1 therapy. Trial Design: Patients eligible for part 2 have histologically confirmed, unresectable, stage III/IV melanoma, have progressed on or after anti-PD-(L)1 treatment, had an anti-PD-(L)1 agent as their most recent therapy, and have not received anti-CTLA-4 treatment. PD-L1 and BRAFV600 mutation status (wild-type and BRAF mutations permitted) must be documented, and serum IL-8 levels will be measured at screening. Patients will be randomized 1:1 to receive BMS-986253 + NIVO + IPI or placebo + NIVO + IPI and stratified by serum IL-8 level, BRAF V600E status, and lactate dehydrogenase level. The dose and frequency of BMS-986253, NIVO, and IPI will be determined by part 1 data. Treatment with BMS-986253 or placebo and NIVO will continue ≤ 3 years or until disease progression or intolerance. The primary objective is to compare progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1 between treatment arms in patients with baseline serum IL-8 levels > 10 pg/mL. Secondary objectives include PFS by BICR in all randomized patients, overall response rates by BICR per RECIST v1.1, overall survival, safety, pharmacokinetic profile, immunogenicity of BMS-986253, and associations of baseline factors with response. Recruitment will continue until ≈170 patients are enrolled. Citation Format: Matteo Simonelli, Emiliano Calvo, Diwakar Davar, Jason Melear, Donald Richards, Matthew Dallos, Martin Gutierrez, Victor Moreno, Thomas Marron, Sylvie Rottey, Angela Orcurto, Susana Barriga, Jessy Fan, Elizabeth Gibson, Santanu Dutta, Vivek Arora, Ignacio Melero. A randomized, double-blind phase 2 evaluation of the anti-IL-8 monoclonal antibody BMS-986253 + nivolumab + ipilimumab vs nivolumab + ipilimumab in patients with advanced melanoma that progressed on/after anti-PD-(L)1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT119.

BackgroundA majority of patients with advanced NSCLC develop disease progression with first-line immune-checkpoint inhibitors (ICI) ± chemotherapy. In the setting of ICI resistance, effective strategies to provide deep and durable responses are urgently needed. Lifileucel (LN-144) and LN-145 are centrally manufactured (cryopreserved drug-product, 22-day manufacturing process) autologous TIL products that have demonstrated activity in advanced melanoma, cervical cancer, and head and neck carcinoma.1–4 Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC.MethodsIOV-COM-202 (NCT03645928) is a phase 2 multicenter, multicohort, open-label study evaluating autologous TIL cell therapy in patients with solid tumors. We report data from Cohort 3B, investigating LN-145 monotherapy in patients with advanced or metastatic NSCLC. Eligibility required 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Treatment included nonmyeloablative lymphodepletion, TIL infusion, and ≤6 interleukin-2 doses. Primary endpoints were safety (incidence of Grade ≥3 treatment-emergent adverse events [TEAEs]) and objective response rate (ORR, investigator-assessed using RECIST v1.1). Exploratory biomarker analyses, including T-cell receptor (TCR) repertoire, were performed.ResultsAs of 24June2021, 28 patients received LN-145 (full-analysis set [FAS]; table 1) and 24 were efficacy-evaluable; all had received prior ICI. TIL were most commonly harvested from lung metastases (57.1%). Safety was consistent with the underlying disease and known TEAE profiles of nonmyeloablative lymphodepletion and interleukin-2. Grade ≥3 TEAEs in ≥30% of patients were thrombocytopenia and anemia. The ORR in the FAS and efficacy-evaluable set was 21.4% (6/28) and 25.0% (6/24; figure 1), respectively. Median duration of response was not reached and 83% (5/6) of responses were ongoing at last follow-up (median study follow-up, 8.2 months). One patient had a complete metabolic response, ongoing at 20.7 months; 2 responses occurred in patients who were PD-L1–negative. All responders received ≥2 prior lines of systemic therapy. Twenty-six patients had TIL available from the final drug-product for TCR repertoire analysis; mean (min-max) number of unique TCR clones was 13,142 (3093–35,734) and Shannon Entropy index was 7.34 (3.7–12). Updated data will be presented.Abstract 458 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable setAbstract 458 Table 1Baseline patient demographic and clinical characteristics; efficacy parametersConclusionsLN-145 was successfully manufactured and one-time treatment produced an expected safety profile and durable responses in heavily pretreated patients with NSCLC, regardless of PD-L1 expression. The activity of LN-145 monotherapy is encouraging and warrants further investigation of LN-145 as a single-agent and in combination in patients with NSCLC in ongoing studies IOV-LUN-202 (NCT04614103) and IOV-COM-202 Cohorts 3A and 3C (3B closed to enrollment).AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.. Thomas SS, et al. J Clin Oncol 2021;39: (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol 2019;37: (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer 2020;8: (suppl; abstract A378).Ethics ApprovalThe study was approved by Advarra Institutional Review Board, approval number Pro00035064 and all study participants provided written consent via signature of the IRB-approved Informed Consent form.

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

Context Immune-checkpoint inhibitors (ICI) have shown significant benefits for overall survival across various cancer types. Patient-reported outcomes (PROs) are assessed in clinical trials as a measure of efficacy. However, it remains unclear to what extent current PRO instruments capture symptoms specific to ICI toxicities. We conducted a systematic review to identify the use and content validity of PRO instruments in ICI clinical trials in oncology. Methods Literature was retrieved from PubMed, Embase, PsycINFO, Medline and CINAHL databases. Articles presenting ICI clinical trials’ PRO results, clinical trial study protocols, and conference abstracts stating the use of PRO measures were assessed. We evaluated the validity of identified instruments by comparing their symptom-related content with the adverse events reported in each ICI clinical trial. Results From database inception until January 2020, we identified 191 ICI clinical trials stating the use of PRO measures of which 26 published PRO results. The cancer-specific EORTC QLQ-C30 and the generic EQ-5D questionnaires were the most widely used instruments, often in combination with disease-specific PROs. Instruments used to report PRO symptom-related toxicities covered 45% of the most frequently reported AEs, whereas 23% of AEs were partially covered and 29% were not covered at all. Of non-covered AEs, 59% referred to the dermatologic system. Partially covered AEs related to endocrine and specific types of pain. Conclusion Despite the high frequency of symptom-related toxicities related to ICI, these events are only partially covered (or not addressed) by current PRO instruments, even when combined. Further research is needed to develop new strategies to tailor PRO instruments to specific ICI toxicities.

BackgroundAdoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising experimental immunotherapy that has shown high objective responses in patients with melanoma. Current protocols use a lymphodepletive chemotherapy before infusion of ex vivo expanded TILs, followed by high-dose interleukin-2 (IL-2). Treatment-related toxicities are mainly attributable to the chemotherapy regimen and to the high-dose IL-2 and are generally reversible. Neurological side effects have rarely been described. Nevertheless, due to improvements in cell production techniques and due to combinations with other immunomodulating molecules, side effects not previously described may be encountered.Case presentationWe report the case of a 53-year-old heavily pretreated patient with melanoma who developed Guillain-Barré syndrome (GBS) 19 days after ACT using autologous TILs, given in the context of a phase I trial. He presented with dorsal back pain, unsteady gait and numbness in hands and feet. Lumbar puncture showed albuminocytological dissociation, and nerve conduction studies revealed prolonged distal motor latencies in median, ulnar, tibial and peroneal nerves, compatible with a GBS. The patient was treated with intravenous immunoglobulins and intensive neurological rehabilitation, with progressive and full recovery at 21 months post-TIL-ACT. Concomitant to the onset of GBS, a cytomegalovirus reactivation on immunosuppression was detected and considered as the most plausible cause of this neurological side effect.ConclusionWe describe for the first time a case of GBS occurring shortly after TIL-ACT for melanoma, even though we could not identify with certainty the triggering agent. The report of such rare cases is of extreme importance to build on the knowledge of immune cellular therapies and their specific spectrum of toxicities.