Patients treated with immune checkpoint inhibitors for HCC should be considered for liver transplantation.

Immunotherapy in organ-transplanted cancer patients: efficacy and risk of organ rejection.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

PD-1 inhibitor as bridge therapy to liver transplantation?

Introduction:Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors.Methods:Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon-γKO mice and WT challenged with B16F10 melanoma and treated with αPD-1 or αPD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell–cell interactions.Results:αPD-1 ICI treated melanoma in young and aged hosts, whereas αPD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon-γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, αPD-1 versus αPD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes.Conclusion:Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain αPD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of αPD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon-γ also affect age-related IC expression and T cell function, meriting additional studies.

BackgroundCurrently, immune checkpoint (ICP) inhibitors are essential drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICP inhibitors, the efficacy and safety of re-challenging the same or another ICP inhibitor remain unclear.Case presentationWe present the case of a patient treated with nivolumab for advanced NSCLC who was previously treated with an ICP inhibitor as the first-line chemotherapy along with heavy cytotoxic chemotherapy. After the failure of five lines of chemotherapy, 3 cycles of nivolumab, as the ICP inhibitor re-challenge, the patient achieved a partial response.ConclusionsThis case might suggest that re-challenging an ICP inhibitor could be clinically active in selected patients with advanced NSCLC who progress after achieving an initial clinical benefit with an ICP inhibitor.

Cutaneous adverse events to immune checkpoint inhibitors in pediatric populations: A retrospective cohort study

Various conversion therapy options have become available to patients with unresectable HCC, but which conversion therapy is optimal for which type of patient is controversial. This study compared the efficacy and safety of TACE alone or combined with immune checkpoint and tyrosine kinase inhibitors. Data were retrospectively compared for patients with initially unresectable HCC who underwent conversion therapy consisting of TACE alone (n=459) or combined with immune checkpoint and tyrosine kinase inhibitors (n=343). Compared to the group that received TACE alone, the group that received triple conversion therapy showed significantly higher rates of overall survival (HR 0.43, 95%CI 0.35-0.53). In addition, triple therapy was associated with significantly longer median progression-free survival (15.9 vs. 8.0mo, p <0.001). These results were confirmed in matched subsets of patients from each group. However, subgroup analysis confirmed the results only for patients with HCC in intermediate or advanced stages, not in an early stage. Those who received triple conversion therapy had a significantly higher rate of hepatectomy after conversion therapy (36.4 vs. 23.5%, p <0.001). Among those who underwent hepatectomy after conversion therapy, triple therapy was associated with a significantly higher rate of complete tumor response (32.1 vs. 11.1%, p <0.001). However, it was also associated with a significantly higher frequency of serious adverse events (35.6 vs. 27.0%, p =0.009). Combining TACE with immune checkpoint and tyrosine kinase inhibitors was associated with significantly better survival and conversion efficacy than TACE alone among patients with intermediate or advanced unresectable HCC.

Metachronous malignancies after response to checkpoint inhibition

Background: TP317 is a novel, highly stable chelate salt of resolvin E1 (RvE1), a pro-resolution mediator that stimulates myeloid cell phagocytosis of tumor debris and attenuates pro-tumoral inflammation through activation of the GPCR, ChemR23 (Sulciner et al., 2018, J. Exp. Med). We hypothesized that RvE1 shifts the immunosuppressive tumor microenvironment (TME) to an immunogenic state, thus offering combination potential with immune checkpoint inhibitors (ICI) in ICI-resistant and ICI-sensitive tumors. Methods: Subcutaneous murine models of lung (LLC), melanoma (B16F10), and pancreatic (Panc02; KPC) tumors were used to investigate TP-317 monotherapy and combinations with ICI. Treatment was initiated when tumors reached 125-240 mm3. Results: In the LLC model (N=5/group), TP317 (0.75 µg QD) inhibited tumor growth (1419 ± 266 mm3) compared to placebo (2348 ± 542 mm3; p=0.068) and anti-PD1 (200 µg IP, Q3D; 3015 ± 730; p=0.078). TP317 + anti-PD1 dual therapy was superior to placebo and anti-PD1 alone (893 ± 166 mm3; p&amp;lt;0.05). In the B16F10 model (N=8/group), TP317 (7.5 µg Q6D) was efficacious compared to placebo (787 ± 367 vs 1964 ± 208 mm3; p&amp;lt;0.01) and comparable to the ICI dual therapy of anti-PD1 + anti-CTLA4 (100 µg 1st dose, 200 µg IP Q3D up to 4 doses). Triple therapy with TP317 + anti-PD1 + anti-CTLA4 was superior to ICI dual therapy (340 ± 91 vs 757 ± 260 mm3; p&amp;lt;0.05). In the Panc02 model (N=8/group), TP317 (0.75 µg Q7D) was efficacious compared to placebo (1148 ± 178 vs 1992 ±165 mm3; p&amp;lt;0.001) and comparable to anti-PD1. TP317 + anti-PD1 dual therapy demonstrated significant anti-tumor activity compared to anti-PD1 alone (329 ± 72 vs 1446 ± 305 mm3; p&amp;lt;0.01). In KRAS-mutant KPC tumors (N=10/group), TP317 (7.5 µg Q6D) demonstrated significant anti-tumor activity compared to placebo (500 ± 110 vs 1314 ± 106 mm3; p&amp;lt;0.001) and was comparable to anti-PD1, while TP-317 + anti-PD1 was superior to anti-PD1 alone (353 ± 82 vs 710 ± 106 mm3; p&amp;lt;0.01). In Panc02 and KPC models, TP317’s anti-tumor efficacy was attenuated by CD8+ T cell or NK cell depletion. Consistent with the depletion study results, RNAseq analysis with cell-type deconvolution showed that TP317 enhanced CD8 and NK cell associated programs in Panc02 and B16F10 tumors, and also promoted macrophage, dendritic cell, B cell and antigen presentation functions in the TME. Conclusions: TP317 monotherapy and ICI combinations significantly inhibited tumor growth in various murine models of cancer. The effects on various immune cell functions and the surprising efficacy of short half-life RvE1 (&amp;lt;2 hours) dosed weekly suggests that TP317 is reprogramming the TME to an immunogenic state. In summary, TP317, an RvE1 drug with a high therapeutic index, has potent single agent efficacy and offers a novel approach in combination with ICI to treat ICI-resistant and ICI-sensitive tumors. Citation Format: Franciele C. Kipper, Eva Rothenberger, Abigail Kelly, Michael Gillespie, Ahmed Attaya, Diane R. Bielenberg, Sui Huang, Lance Pflieger, Frank Sciavolino, Aaron Mathias, Wayne Klohs, John Parkinson, Gary Mathias, Dipak Panigrahy. TP317, a first-in-class resolvin E1 small molecule, potentiates the efficacy of immune checkpoint (ICI) inhibitors in ICI-resistant and ICI-sensitive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1135.

Immune checkpoint inhibitors (ICI) and BRAF and MEK inhibitors (BMi) have improved survival in metastatic melanoma (MM). However, the experience of long-term responders remains undescribed. This study characterised survivorship issues faced by long-term responders to ICI or BMi. Patients with MM, aged ≥ 18years old, ≥ 6months post-ICI or BMi initiation with an objective response or stable disease. A 72-question survey assessed physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports. One hundredand five of 120 (88%) patients completed the survey (ICI 69/BMI 36). For the ICI cohort, 39 (57%) were receiving ongoing treatment, 17 ceased due to toxicity and 13 due to a sustained response. For the BMi cohort, 31 (85%) were receiving ongoing treatment, 4 ceased due to toxicity and 1 due to a sustained complete response. At data cut-off on 18 December 2018, median PFS (range) was 2.5years (1.3-8.5) for ICI and 3.1years (0.6-7.3) for BMi. Long-term toxicities included dry/itchy skin (ICI 51, 74%/BMi 25, 69%), arthralgias (ICI 30, 58%/BMi 23, 64%) and fatigue (ICI 62, 90%/BMi 33, 92%). Psychological morbidity was common, including anxiety awaiting results (ICI 50, 72%/BMi 29, 81%), fear of melanoma recurring or progressing (ICI 56, 81%/BMi 31, 86%) or death (ICI 44, 64%/BMi 26, 72%). MM survivors experience chronic treatment toxicities and frequently report psychological concerns. Survivors may benefit from discussions regarding long-term toxicities and tailored psychological supports.

PurposeThis review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune checkpoint and DNA repair inhibitors.MethodsA literature search was conducted in PubMed using the terms (“DNA repair* and DNA damage response* and intracellular immune response* and immune checkpoint inhibition* and radio*”) until January 31, 2023. Articles were manually selected based on their relevance to the topics analyzed.ResultsModern radiotherapy offers a wide range of options for tumor treatment. Radiation-resistant subpopulations of the tumor pose a particular challenge for complete cure. This is due to the enhanced activation of molecular defense mechanisms that prevent cell death because of DNA damage. Novel approaches to enhance tumor cure are provided by immune checkpoint inhibitors, but their effectiveness, especially in tumors without increased mutational burden, also remains limited. Combining inhibitors of both immune checkpoints and DNA damage response with radiation may be an attractive option to augment existing therapies and is the subject of the data summarized here.ConclusionThe combination of tested inhibitors of DNA damage and immune responses in preclinical models opens additional attractive options for the radiosensitization of tumors and represents a promising application for future therapeutic approaches.

Background: Over 2 million women develop breast cancer globally every year despite immense advances in disease biology, diagnostic strategies and novel treatment options. The deeper knowledge of disease biology and genomic landscape has fostered a broader mechanistic approach to patients and their therapeutic choices. Many preclinical and clinical studies suggest a benefit of combining PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICPi) in patients with homologous recombination deficiency (HRD) intact and mutated cancers. However, similar to the varied benefits of either drug class based on tissue and mutational context, the benefits of such combination are strongly variable based on tumor type, tissue and mutation context. Methods: To study how select HRD mutations respond to a combination of a PARPi inhibitor with an ICPi, we used CRISPR engineering to functionally impair or repress BRCA1, BRCA2, ATM, CHEK2, PALB2 in different mouse breast cancer cell lines. EMT6 and 4T1 cells were engineered to expressed deactivated cas9 nuclease (dcas9) fused to the repressor domain Kruppel-associated- box (KRAB) and mcherry florescent protein. The dcas9-KRAB-mcherry breast cancer cells were further engineered to express BFP-tagged guide RNAs targeting selected genes under a doxycycline inducible tet-on system. After establishing functional loss/repression of the targeted HRD mutations, cells were then implanted in the mammary fat pad of balb/cJ mice and treated with PARPi and ICPi to determine the ICPi, PARPi and their combination induced changes in inflammatory signals and their association with therapy response. Results: Induced suppression of BRCA1 and PALB2 in these breast cancer cells showed exquisite sensitivity to PARPi (IC50 0.01 uM and 0.098 uM) and diminishing sensitivity to PARPi in BRCA2 and ATM (IC50 0.16 uM and IC50 0.28 uM). In contrast, inducible suppression of CHEK2 showed resistance to PARPi versus parental EMT6 cells (IC50 13.9 uM versus 5.3 uM). Evaluation of changes in expression levels of PDL1 and select chemokines including CCL2, CCL5, CXCL9, CXCL10 and CXCL11 suggest a differential response to PARPi depending on specific HRD mutations. HRD mutations and tissue-context will be further characterized in combination therapy of ICPi and PARPi. Conclusion: Using inducible suppression of HRD function in an immune competent mouse breast cancer model helps to understand the differential role of individual HRD mutations (BRCA1, BRCA2, ATM, CHEK2, PALB2) in altering inflammatory signals in response to PARPi and ICI. This data may guide the clinical development of such combination in breast cancer and other cancers. Citation Format: Sibapriya Chaudhuri, Scott Thomas, Luika Timmerman, Pamela Munster. Deciphering the role of homologous recombination deficiency mutations in the response to combined immune checkpoint and PARP inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B019.

Drug-induced hypersensitivity syndrome like reaction with angioedema and hypotension associated with BRAF inhibitor use and antecedent immune checkpoint therapy

Transplant-associated cancer in the era of immune checkpoint inhibitors: Primum non nocere.

Over the past decade, the development and use of targeted immunotherapies in the treatment of solid organ and hematologic malignancies have revolutionized the field of oncology. Whereas prior cancer treatments had largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy, targeted immunotherapy unleashes our own adaptive immune response in preventing tumor progression. The discovery that cancers overexpress receptors designed to suppress adaptive T lymphocyte immune capabilities led to the development of so-called immune checkpoint inhibitors. Antibodies that target the cytotoxic T lymphocyte–associated protein-4, the programmed cell death 1 protein, or its ligand programmed death ligand 1 have been shown to enhance adaptive T cell activity in the tumor microenvironment. AKI can be a dreaded and clinically important event during therapy that often prompts an interruption or even discontinuation of treatment. Perhaps thankfully, AKI was thought to be a relatively rare event associated with checkpoint inhibitors. Early estimates of AKI incidence were approximately 1%–2% in patients treated with a single agent (ipilimumab, nivolumab, or pembrolizumab) and 4.5% in those treated with the combination of nivolumab plus ipilimumab (1–3). The incidence of severe AKI (greater than or equal to threefold increase in serum creatinine or dialysis) was <1% with single agents and 1.6% with the combination of nivolumab plus ipilimumab (1–3). Regardless, as use of checkpoint inhibitors grows, recognition and understanding of its clinical pattern of nephrotoxic injury are urgently needed. The classic mechanism of kidney injury from checkpoint inhibitors is that of acute interstitial nephritis (AIN). In 2016, Cortazar et al. (1) reported a patient series of 13 patients across seven centers who underwent a kidney biopsy for severe AKI during checkpoint inhibitor use. The most prevalent pathologic lesion was acute tubulointerstitial nephritis (12 of 13) characterized by diffuse interstitial infiltrates of CD3+ and CD4+ T lymphocytes (with paucity of plasma cells and eosinophils). Importantly, this patient series was the first to provide evidence of efficacy with steroids. Among the ten patients treated with steroids, nine had at least partial improvement in kidney function. AIN is now established as the primary kidney example of numerous potential immune-related adverse events (irAEs) that can affect virtually any off-target organ, including gastrointestinal tract (colitis and enteritis), liver (hepatitis), skin (dermatitis), endocrine glands (adrenalitis and thyroiditis), and lung (pneumonitis) among others, thought to represent upregulated immune system activation (4). In this issue of CJASN, Seethapathy et al. (5) leverage comprehensive clinical data from a large tertiary oncology referral center to describe the phenotypes and predictors of AKI among just over 1000 patients treated with checkpoint inhibitors between 2011 and 2016. Among this cohort, 82 patients (8%) experienced the primary outcome of sustained AKI—defined as at least 1.5-fold rise in serum creatinine (from baseline) that persisted for ≥3 days within 1 year of treatment. Patient charts were carefully adjudicated by the investigator-nephrologists to determine whether each sustained AKI event was most likely to be "checkpoint inhibitor related" versus from another etiology (hemodynamic AKI/acute tubular necrosis, obstructive AKI, or undetermined). AKI was attributed to checkpoint inhibitor use in 30 patients (3%), occurring at a mean time of 3.5 months after commencement of therapy. The study is strengthened by its large sample size (purportedly the largest "real world" clinical cohort to date) with a wide variety of malignancies being treated; completeness and granularity in health record data, including the presentation of detailed patient summaries of checkpoint inhibitor–related AKI and descriptions of concurrent irAEs (provided in supplemental table 3 of Seethapathy et al. [5]); and its key capture of concomitant medications to elucidate a potentially important association. These data build on earlier biopsy patient series and pooled analyses of clinical trial data to better delineate a contemporary understanding of the epidemiology of AKI associated with immune checkpoint inhibitor treatment. Several key findings should be highlighted (5). The data here show that the rates of AKI during checkpoint inhibitor therapy seem to be higher than earlier reports (1–3): overall AKI incidence of 17%, sustained AKI incidence of 8%, and checkpoint inhibitor–related AKI of 3% within 1 year of treatment. Baseline kidney function did not seem to be predictive of AKI, thus arguing that the checkpoint inhibitor therapy may be relatively safe in patients with baseline CKD (although it is difficult to ascertain if there is selection bias upfront; i.e., clinical exclusion of patients with lower kidney function from initiation of therapy). Checkpoint inhibitor–related AKI (i.e., patients with suspected AIN cases) occurred on average ≥100 days after therapy commencement. This corroborates prior reports (1,6) also showing a delayed onset of AKI after checkpoint inhibitor initiation, suggesting a mechanism of AIN separate from or beyond direct immunogenicity of checkpoint inhibitors or their metabolites (7). Lastly, a key finding that emerged from this study (5) is the association between baseline use of a proton pump inhibitor (PPI) and risk of AKI after prolonged exposure to checkpoint inhibitor therapy. In multivariable survival analysis taking into account competing risk of death, the investigators found that baseline PPI exposure was a strong risk factor for sustained AKI after 2.5 months of follow-up (adjusted hazard ratio, 2.85; 95% confidence interval, 1.34 to 6.08). This finding substantiates the observation from a small patient series in which five of six patients with biopsy-proven AIN from programmed cell death 1 protein inhibitor treatment had preceding exposure to PPIs (8). Again, the delayed onset of AKI after weeks to months of immune checkpoint exposure in the context of chronic PPI use points to a postulated mechanism of AIN in which checkpoint inhibitors may cause a disruption in longstanding tolerance of memory T cells primed toward PPIs. Still, better mechanistic understanding of checkpoint inhibitor–associated AIN and further validation of PPI exposure as a risk factor in other cohorts are needed before we implement widespread practice changes to strictly limit the use of PPIs before starting checkpoint inhibitors. Significant limitations and questions remain. In this study (5), only one patient with a case of checkpoint inhibitor–related AKI was confirmed by a kidney biopsy (showing AIN). Therefore, these results assume that chart review was sufficient in accurately adjudicating patients with checkpoint inhibitor–associated AIN from other phenotypes of AKI using additional data, such as concurrent occurrence of nonkidney irAEs and response to steroids (along with pyuria, which was not always present significantly on urine microscopy). The low rate of biopsy in this study (5) may reflect lower awareness of AIN as a complication during earlier parts of the study period, but it may be fairly representative of common sense clinical practice elsewhere given inherent risks associated with kidney biopsies, especially in patients with AKI cases that are reversed readily. Recently published and slightly more contemporary biopsy patient series examining nephrotoxicities associated with checkpoint inhibitors have highlighted, interestingly, a wide range of glomerular lesions (some accompanied by interstitial inflammation) in one study (6) and high frequency of pure tubular injury (without significant interstitial nephritis) in another (9). In the absence of validated predictive biomarkers to help phenotype the type of kidney injury, it remains prudent for clinicians to pursue timely tissue diagnosis, especially in cases of severe AKI without other clear kidney insults, to help guide appropriate therapy. Because of the time period from which the study population was derived, the study is also hindered a bit by the very small number of patients receiving programmed death ligand 1 inhibitors (4%) or a combination of checkpoint inhibitors. The usual caveats of retrospective, observational analyses using clinically obtained data apply. Because the study population does not arise from a strict integrated health care system, there is potential for ascertainment bias and underestimation of AKI incidence along with undercapture of important predictors. Despite the large overall sample size, the ultimately small number of patients with AKI (and even smaller numbers of potential checkpoint inhibitor–associated AKI) limits the investigators' ability to perform more extensive adjustments to minimize confounding. Therefore, the novel elucidation of PPIs as a risk factor for AKI in this setting may still suffer from residual confounding (and therefore, should to be validated consistently across other cohorts). Nevertheless, this study by Seethapathy et al. (5) represents a significant step forward in the field of immune checkpoint inhibitor–associated nephrotoxicity and onconephrology in general. By leveraging electronic health record data from a large academic center, the investigators are able to reasonably ascertain the real world incidence of AKI using consistent definitions, describe the timing and phenotypes of AKI, and shed light on a potentially important association between PPI use and checkpoint inhibitor–associated AKI that smaller case series (include patients who developed AKI or patients who received biopsies) are unable to do. In addition to validating PPIs as a risk factor, future studies should explore additional risk factors, including how genetic determinants of autoimmune diseases may predict checkpoint inhibitor–associated AKI. Prospective studies with standardized collection of sera and urine may help to establish biomarkers to help identify AIN in this setting without tissue diagnosis (10). In terms of treatment of checkpoint inhibitor–associated AKI/AIN, we also need more data on optimal steroid dosing/length/tapering along with answers on if (and when and how) to rechallenge patients with checkpoint inhibitors after AKI, especially when potential oncologic benefits of treatment may outweigh kidney function preservation. As both oncologists and nephrologists face more AKI with ongoing growth in use of immune checkpoint inhibitors, it is now time to push beyond case reports and series. Disclosures Dr. Carlos has nothing to disclose. Dr. Hsu reports receiving consultancy fees from AstraZeneca and DaVita.