The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of ...patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Furthermore, the resistance mechanisms appear to be highly heterogeneous. Here, we discuss recent human cancer data identifying mechanisms of resistance to anti-PD therapy. We review evidence for immune-based resistance mechanisms such as loss of neoantigens, defects in antigen presentation and interferon signaling, immune inhibitory molecules, and exclusion of T cells. We also review the clinical evidence for emerging mechanisms of resistance to anti-PD therapy, such as alterations in metabolism, microbiota, and epigenetics. Finally, we discuss strategies to overcome anti-PD therapy resistance and emphasize the need to develop additional immunotherapies based on the concept of normalization cancer immunotherapy.
Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid ...cancer expressing programmed death ligand 1 (PD-L1).
Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1.
Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7-34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval CI, 1-29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2-14 months); median overall survival was not reached (95% CI, 22 months to not reached).
Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings.
Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being ...evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.
Une patiente de 50 ans a présenté une polyradiculonévrite (PRN) dysautonomique pure sans atteinte motrice ou sensitive dans le cadre de mélanome métastatique traité par anti-PD-1.
La patiente ...présenta en septembre 2018 un mélanome nodulaire du vertex muté BRAF V600K, avec des métastases pulmonaires découvertes en juillet 2019 et traitées par 4 cures de pembrolizumab (anti-PD-1), arrêté en octobre 2019 devant la découverte de métastases cérébrales. Elle présenta en décembre 2019 un syndrome occlusif en rapport avec un iléus paralytique, répondant à des hautes doses de corticoïdes, ainsi que d’autres signes dysautonomiques : une hypotension orthostatique sévère, une bradycardie ainsi qu’une rétention aiguë d’urine. À l’ENMG, il n’y avait pas de signe de neuropathie des membres, mais une atteinte dysautonomique d’origine neurologique avec une altération des réflexes cutanés sympathiques. L’absence d’anomalie à la ponction lombaire et de nouvelle métastase à l’IRM cérébrale, la négativité des anticorps antigangliosides et antineuronaux, et la glycémie normale ont permis d’exclure les diagnostics différentiels et d’évoquer une complication liée aux anti-PD1. Un traitement par Ig IV 2g/kg a été initié. Mais, devant l’absence d’amélioration, une intensification thérapeutique par échanges plasmatiques a été décidée, avec un rythme initial hebdomadaire, suivi d’un espacement progressif, permettant une résolution de la symptomatologie.
Les complications neurologiques des immunothérapies sont rares (< 5 %) avec une fréquence augmentée si association anti-CTLA4 et PD-1 (12 %). La physiopathologie est mal connue. Les atteintes sont variées : atteintes centrales (myélites, encéphalites) ou périphériques (PRN, syndromes myasthéniques). Le traitement repose sur un arrêt de l’immunothérapie et une corticothérapie, voire des immunosuppresseurs. Le pronostic post-traitement est généralement favorable.
Les complications neurologiques des immunothérapies sont rares mais peuvent être sévères. Elles représentent un véritable challenge diagnostique et thérapeutique compte tenu de l’essor des immunothérapies.
The commensal microbiota has been implicated in the regulation of a diverse array of physiological processes, both within the gastrointestinal tract and at distant tissue sites. Cancer is no ...exception, and distinct aspects of the microbiota have been reported to have either pro- or anti-tumor effects. The functional role of the microbiota in regulating not only mucosal but also systemic immune responses has led to investigations into the impact on cancer immunotherapies, particularly with agents targeting the immunologic checkpoints PD-1 and CTLA-4. Microbial sequencing and reconstitution of germ-free mice have indicated both positive and negative regulatory bacteria likely exist, which either promote or interfere with immunotherapy efficacy. These collective findings have led to the development of clinical trials pursuing microbiome-based therapeutic interventions, with the hope of expanding immunotherapy efficacy. This review summarizes recent knowledge about the relationship between the host microbiota and cancer and anti-tumor immune response, with implications for cancer therapy.
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Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein ...4 (CTLA4), but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.
Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.
One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%).
Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.
•The incidence of delayed irAEs >12 months after commencing anti-PD-1 was 5.3%.•Delayed irAEs occurred in 118 patients; these were often high grade (39% G3+) including two delayed irAE-related deaths.•Delayed irAEs were often difficult to manage; 68% required steroids and 23% required an additional immunosuppressive agent.•Most occurred during anti-PD-1 therapy (74%), but delayed irAEs were also reported up to 26 months after stopping anti-PD-1.
Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in ...HIV-associated cHL (HIV-cHL).
We retrospectively identified patients with HIV-cHL from the “Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)” database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification.
We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95).
Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.
There are limited data on PD-1 blockade in HIV-associated classical Hodgkin lymphoma (HIV-cHL). We retrospectively identified 23 patients with HIV-cHL safely treated with PD-1 blockade with a response rate of 83% that did not differ by CD4+ T-cell count. Our data support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.
BACKGROUNDMucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the ...efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODSA retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTSIn total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab 40%, 95% confidence interval (CI) 29% to 54% compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONSMM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.
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