USC scientist Ya-Wen Chen receives American Lung Association grant to advance stem cell-based lung therapies – USC News

USC Stem Cell scientist Ya-Wen Chen hopes to pioneer a new approach to regenerating damaged lung tissue, with support from a Catalyst Grant from the American Lung Association (ALA). The award provides $50,000 year for up to two years.

For many patients with chronic lung diseases, the only available treatment is transplantationa difficult, dangerous surgery that involves challenges ranging from the severe shortage of donor organs to immune rejection, said Chen, who is an assistant professor of medicine, and stem cell biology and regenerative medicine at USC. Even patients who are lucky enough to receive donor organs only have a 10 to 20 percent survival rate at 10 years. If we can encourage these patients own cells to repair damage and heal their lungs, we could dramatically improve this prognosis.

With this goal in mind, Chen is using human stem cells to generate rudimentary lung-like structures known as lung bud organoids. Within these organoids, Chens group will probe how a specific population of cells repairs the tiny gas-exchange interfaces called alveoli in damaged lungs.

Specifically, Chen is interested in a population of cells known as distal small airway epithelial progenitors or SAEPs, which could have the potential to improve lung function in patients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). A group of lung diseases that includes chronic bronchitis and emphysema, COPD affects at least 16 million Americans and is the third leading cause of death in the U.S. An additional 200,000 Americans are living with IPF, a progressive, incurable and often deadly disease that, for unknown reasons, causes scar tissue to form in the lungs, impeding breathing.

Our ultimate goal is to leverage patients existing stem and progenitor cells to promote healing through a non-surgical, regenerative approach, said Chen, a member of the USC Hastings Center for Pulmonary Research, as well as USCs stem cell research center.

Chen is one of 98 scientists to receive research support from the ALA, which has committed $11.55 million total to support scientific investigations aimed at reducing the burden of lung disease.

Despite the fact that the pandemic poses significant economic challenges, said ALA President and CEO Harold Wimmer, the American Lung Association is prioritizing research and significantly increasing award funding to help improve the lung health of all Americans.

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USC scientist Ya-Wen Chen receives American Lung Association grant to advance stem cell-based lung therapies - USC News

[Full text] Successful Use of Nivolumab in a Patient with Head and Neck Cancer Aft | OTT – Dove Medical Press

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the major causes of cancer-associated illness and death, with more than 600,000 newly diagnosed cases worldwide each year1 and a continuously increasing incidence rate.2 HNSCC includes cancers of the oral cavity, pharynx, and larynx. The anatomical structures of the head and neck can be damaged by the tumor itself or treatments such as surgical resection and chemoradiotherapy, which sometimes cause speech, swallowing, and breathing impairments.3,4 Patients with HNSCC have been shown to bear greater psychological distress than those with other types of cancer.5

Despite the currently available therapies, patients with advanced HNSCC still experience poor outcomes.68 For example >50% of patients with locoregionally advanced HNSCC experience recurrence or metastases development within 3 years of treatment.911 Treatment options for patients with the recurrent and metastatic disease following progression after a platinum-based regimen are limited, and the median overall survival of such patients is less than 7 months.1215

The recurrence and metastasis of HNSCC are facilitated by immune evasion;16 therefore, as one of the methods to inhibit immune evasion, the use of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway inhibitors is considered effective in the treatment of recurrent HNSCC.1719 Nivolumab, a fully human IgG4 antiPD-1 monoclonal antibody, has shown remarkable antitumor efficacy and safety when administered to patients with recurrent HNSCC whose disease had progressed within 6 months of platinum-based chemotherapy;19 Furthermore, nivolumab treatment has been shown to improve the quality of life of these patients.20 However, PD-1 inhibitors can upregulate T cells in vivo, which may lead to the development of graft-versus-host disease (GVHD) in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).2123 To the best of the authors knowledge, no studies have investigated the safety and efficacy of nivolumab in patients with HNSCC after allo-HSCT. Here, we report the case of a patient who experienced excellent control of left buccal squamous cell carcinoma with nivolumab after the failure of platinum-based chemotherapy despite receiving allogeneic bone marrow transplantation.

Without any family history of tumor, a 33-year-old man was diagnosed with Philadelphia chromosome-positive T cell acute lymphoblastic leukemia on March 19, 2014. He received one course of vincristine and prednisone therapy and four courses of vincristine, daunorubicin, cyclophosphamide, and prednisone therapy. He was in complete remission at the end of therapy. Subsequently, allogeneic bone marrow transplantation was performed; the donor was his human leukocyte antigen (HLA)-haploidentical sibling (sister). He experienced chronic GVHD (c GVHD) of the oral cavity and skin 3 months after transplantation, for which he was treated with steroid hormone- and cyclosporine-based therapies. Skin rejection lasted for more than 3 years. Imatinib mesylate was administered for 2 years after transplantation, and his leukemia was well controlled.

In August 2018, the patient developed an ulcer of approximately 0.5 0.5 cm size in the left buccal mucosa; the ulcer was slightly painful and covered with white moss. In September 2018, the patient was admitted to Peking University Stomatological Hospital, where a biopsy of the buccal mucosa was performed. The pathology results showed the presence of squamous cell carcinoma in the left cheek. Unfortunately, this patient was not a right candidate for HNSCC in terms of exposure to risk factors, such as long terms of smoking and drinking. On October 10, 2018, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (CT) showed that the mass in the left cheek was metabolically active, which is consistent with the activity of a malignant tumor. One course of an adjuvant therapy regimen (nimotuzumab [200 mg d0] + docetaxel [60 mg d1, 8]+ nedaplatin [60 mg d2, 3]) was administered on October 26, 2018. Following this, the patient developed degree II thrombocytopenia and redness, swelling, and ulceration of the cheek, which had discharge with a peculiar smell. On November 29, 2018, a head and neck CT scan showed a left buccal malignant tumor with the destruction of the neighboring mandibular bone and lymph node enlargement in the left submaxillary region and right carotid sheath. The CT examination revealed disease progression. Following a multidisciplinary consultation in our hospital, surgery was not recommended; instead, a chemotherapy-based comprehensive treatment was recommended as a better option for the patient. The patient received chemotherapy with albumin paclitaxel (200 mg d1, 8)+ bleomycin (15,000 units d2, 9) from November 30, 2018 to January 9, 2019. On another CT scan, the curative effect was evaluated as partial remission (showed in Video 1, Figure 1A); subsequently, two courses of a chemotherapy regimen comprising nivolumab (140 mg d1) + albumin paclitaxel (200 mg d1, d8) were administered. A CT examination showed stable disease (SD) on March 12, 2019, following which the patient was administered 120 mg of nivolumab once every 2 weeks from March 15 to May 23, 2019. Another CT examination was performed on May 28, 2019 (showed in Video 2, Figure 1B). During the therapy course, the related tumor markers showed an overall downward trend, the new metastases did not appear, the patients status became better than before. Subsequently, another CT examination performed in August 02, 2019 showed the extent of the tumor was obvious reduction than before (showed in video 3, Figure 1C). And the corresponding CT report in August 02, 2019 was described as follows Compared with the CT on 28 May, 2019, the extent of the tumor in the left cheek became obviously smaller, the tubercle in the left submandibular and the lymph nodes in the left neck also became smaller. There were no other significant changes in this image. Most importantly, the patient did not develop any form of GVHD following nivolumab administration.

Figure 1 Head and neck CT images showing tumor before (A) and after treatment with nivolumab (B, C, respectively).

Abbreviation: CT, computed tomography.

Note: The arrows indicate the maximum length diameter of tumor or tumor site.

Reliable data on the clinical safety and efficacy of nivolumab in the treatment of recurrent or metastatic HNSCC have been obtained in a Phase III randomized clinical trial (CheckMate 141).19 In this trial, 361 patients with recurrent HNSCC for whom disease had progressed within 6 months after platinum-based chemotherapy were enrolled between May 29, 2014, and July 31, 2015. The median follow-up duration for overall survival (OS) was 5.1 months (range, 016.8 months). OS was significantly greater in patients randomized to receive nivolumab than in those who received standard second-line, single-agent systemic therapy with either methotrexate, docetaxel, or cetuximab (hazard ratio, 0.70; 97.73% confidence interval (CI), 0.510.96; P = 0.01). The median OS was 7.5 months (95% CI, 5.59.1) in the nivolumab group versus 5.1 months (95% CI, 4.06.0) in the standard therapy group. The one-year survival was also greater in patients who received nivolumab than in those who received standard therapy (36.0%vs. 16.6%). Furthermore, the response rate was higher in those who received nivolumab than in those who received standard therapy (13.3% vs 5.8%); however, the median progression-free survival was not significantly different between the groups (2.0 vs 2.3 months; P=0.32). In this study, patients who were treated with nivolumab had a longer OS than those treated with standard therapy, regardless of tumor PD-L1 expression or p16 status. Grade 3 or 4 treatment-related adverse events occurred in 13.1% of patients who received nivolumab and 35.1% of those who received standard therapy. Physical function, role functioning, and social functioning were stable in the nivolumab group, whereas they were substantially worse in the standard therapy group.20 Moreover, among Asian patients, the survival benefits were consistent with the global group.24

It was unclear whether nivolumab could be used in patients with recurrent HNSCC after allo-HSCT, though Khaddour et al proved the efficacy and safety of Pembrolizumab in patients who underwent allo-HSCT after relapsed and refractory Szary Syndrome and cutaneous squamous cell carcinoma.25 However, some case reports (Table 1) and clinical trials (Table 2) have reported the efficacy and safety of nivolumab when administrated to patients with recurrent hematological malignancies (mostly Hodgkins lymphoma) after allo-HSCT.

Table 1 Case Reports of Nivolumab Use After Allo-HSCT

Table 2 Studies on Nivolumab Use After Allo-HSCT

In Herbaux et al, nivolumab (3 mg/kg, once every 2 weeks) was administered to 20 patients with Hodgkins lymphoma who experienced relapse after allo-HSCT. The overall response rate was 95%, the 1-year progression-free survival rate was 58.2%, and the 1-year OS rate was 78.8%.26 Compared with other treatment options, nivolumab was more effective in these patients.2730 Haverkos et al reported results after a median follow-up duration was 428 days (range, 133833 days). After treatment with PD-1 inhibitors [nivolumab 3 mg/kg, once every 2 weeks (n = 28) and pembrolizumab (n =3)], the overall response rate of 31 patients with relapsed lymphoma after allo-HSCT was 77%, the median progression-free survival was 591 days (range,400644 days), and 68% of the patients survived to the end of the study.23 These two studies showed that nivolumab is effective when administered to patients with recurrent blood cancers after allo-HSCT, which is consistent with the results of several other case reports3134 and case series.35,36 The PD-1/PD-L1 pathway plays a key role in the regulation of the balance among T cell activation, T-cell tolerance, and immune-mediated tissue damage. This pathway protects healthy cells from excessive inflammatory or autoimmune responses.37,38 Some studies have shown that the activation of the PD-1/PD-L1 pathway can reduce acute and chronic GVHD, whereas its blockade can accelerate the graft-versus-host response and increase the associated mortality.21,22,39 It is unclear whether the PD-1 inhibitor nivolumab increases the risk of GVHD and the associated mortality in patients after allo-HSCT.23,26 Some clinical studies and case reports have shown that nivolumab treatment-related GVHD and consequent death in patients after allo-HSCT might be affected by the following factors. First, GVHD after antiPD-1 treatment has been observed most frequently in matched sibling donor transplants; for which Haverkos et al reported an incidence of 75%.23 In a Phase I pilot study, without GVHD or G3/G4 immune toxicity after receiving multiple doses of nivolumab was only among one patient whose donor source was Haploidentical+cord blood Fludarabine.40 Second, a history of GVHD, especially for the acute GVHD, may lead to an increased risk of nivolumab treatment-related GVHD after allo-HSCT. In a French cohort, all patients who presented with acute GVHD after nivolumab treatment had a prior history of acute GVHD, among which three patients presented with steroid-refractory nivolumab-induced GVHD, and GVHD was not observed among patients without a history of GVHD.26 This phenomenon was also observed in Steinerovs medical report.41 In the study by Haverkos et al, 63% of patients with a history of GVHD prior to antiPD-1 treatment developed treatment-emergent GVHD after receiving antiPD-1.23 Third, the shorter the interval between transplantation and nivolumab use, the greater the risk of GVHD. In the study by Herbaux et al, the median intervals between transplantation and nivolumab use in cases with the presence and absence of GVHD were 8.5 months and 28.5 months, respectively.26 In another study by Wang et al, the reported four patients all experienced immune-related adverse events following nivolumab treatment and the median time from transplantation to nivolumab use was 7.8 months.40 Fourth, dose is a risk factor for nivolumab treatment-related GVHD. In a case report, chronic skin GVHD was observed when the dose of nivolumab was adjusted from 0.5 mg/kg to 2 mg/kg.33 Other factors, such as immunosuppressive therapy at the time of nivolumab administration, may also influence nivolumab treatment-related GVHD. Recently, a comprehensive literature review was launched by Awais et al to assess the safety and efficacy of the use of checkpoint inhibitors (ipilimumab, nivolumab and pembrolizumab) in blood cancers before and after allo-HSCT. Collective data showed that checkpoint inhibitors use after allo-HSCT for post-transplant relapse had higher efficacy but the risk of GVHD was significant. Moreover, the investigation indicated that higher drug doses, shorter intervals between checkpoint inhibitors exposure and allo-HSCT and prior history of GVHD had a positive correlation with the risk of GVHD.42

In the present case, HNSCC was effectively controlled without any nivolumab treatment-related acute or chronic GVHD after nivolumab administration, while the weight loss being the only adverse event. After comprehensive analysis, we found that many factors may impede the development of nivolumab treatment-related GVHD in our patient. On one hand, the appropriate donor, no use of checkpoint inhibitors prior to allo-HSCT, the long interval between nivolumab administration and allo-HSCT (36 months) and the standard dose use of nivolumab were the negative factors for GVHD development. On the other hand, the chronic GVHD of the oral cavity and skin before nivolumab use might lead to the development of GVHD. However, it remained unknown what role the immunosuppressant therapy played in the occurrence of GVHD, though we definitely known that immunosuppressant was administered more than 2 years after allo-HSCT and discontinued for 2 years before treatment with nivolumab in our patient. Finally, whether the two primary cancers in our case affected the efficacy and safety of nivolumab by some unknown pathways were unclear, which needed further exploration.

Nivolumab has been shown to be effective in patients with HNSCC for whom platinum-based therapy has failed. However, little is known about the efficacy and safety of nivolumab in patients with HNSCC who have undergone allo-HSCT. Our case report shows that nivolumab could be used effectively and safely in such patients, however, more clinical trials are required to confirm these results.

This study was approved by the Medical Ethics Committee of Tianjin Medical University Cancer Institute and Hospital. The authors state that they have obtained verbal and written informed consent from the patient for the inclusion of their medical and treatment history within this case report.

This work was supported by the Tianjin Science and Technology Commission (18ZXXYSY00070), Key Task Project of Tianjin Health and Family Planning Commission (16KG128), Anticancer Key Technologies R&D Program of Tianjin (12ZCDZSY16200), and Natural Science Foundation of Tianjin (18JCYBJC91600).

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359E386. doi:10.1002/ijc.29210

2. Jakobsen KK, Gronhoj C, Jensen DH, et al. Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014. Acta Oncol. 2018;57:11431151. doi:10.1080/0284186X.2018.1438657

3. Sobecki-Ryniak D, Krouse HJ. Head and neck cancer: historical evolution of treatment and patient self-care requirements. Clin J Oncol Nurs. 2013;17(6):659663. doi:10.1188/13.CJON.659-663

4. Licitra L, Mesia R, Keilholz U. Individualised quality of life as a measure to guide treatment choices in squamous cell carcinoma of the head and neck. Oral Oncol. 2016;52:1823. doi:10.1016/j.oraloncology.2015.10.020

5. Singer S, Krauss O, Keszte J, et al. Predictors of emotional distress in patients with head and neck cancer. Head Neck. 2012;34(2):180187. doi:10.1002/hed.21702

6. Licitra L, Felip E. Squamous cell carcinoma of the head and neck: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):121122. doi:10.1093/annonc/mdp149

7. Adelstein D, Gillison ML, Pfister DG, et al. NCCN guidelines insights: head and neck cancers, version 2.2017. J Natl Compr Canc Netw. 2017;15(6):761770. doi:10.6004/jnccn.2017.0101

8. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(45):309316. doi:10.1016/j.oraloncology.2008.06.002

9. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):19451952. doi:10.1056/NEJMoa032641

10. Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011;100(1):3340. doi:10.1016/j.radonc.2011.05.036

11. Tanvetyanon T, Padhya T, McCaffrey J, et al. Postoperative concurrent chemotherapy and radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2015;37(6):840845. doi:10.1002/hed.23684

12. Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised Phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer. 2004;40(14):20712076. doi:10.1016/j.ejca.2004.05.019

13. Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer. 2008;112(12):27102719. doi:10.1002/cncr.23442

14. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol. 2013;31(11):14051414. doi:10.1200/JCO.2012.45.4272

15. Saloura V, Cohen EEW, Licitra L, et al. An open-label single-arm, phase II trial of zalutumumab, a human monoclonal anti-EGFR antibody, in patients with platinum-refractory squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol. 2014;73(6):12271239. doi:10.1007/s00280-014-2459-z

16. Ferris RL. Immunology and Immunotherapy of head and neck cancer. J Clin Oncol. 2015;33(29):32933304. doi:10.1200/JCO.2015.61.1509

17. Chow LQM, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34(32):38383845. doi:10.1200/JCO.2016.68.1478

18. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956965. doi:10.1016/S1470-2045(16)30066-3

19. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):18561867. doi:10.1056/NEJMoa1602252

20. Harrington KJ, Ferris RL, Blumenschein G Jr, et al. Nivolumab versus standard, single-agent therapy of investigators choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, Phase 3 trial. Lancet Oncol. 2017;18:11041115. doi:10.1016/S1470-2045(17)30421-7

21. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 2003;171:12721277. doi:10.4049/jimmunol.171.3.1272

22. Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122:30623073. doi:10.1182/blood-2013-05-500801

23. Haverkos BM, Abbott D, Hamadani M, et al. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130:221228. doi:10.1182/blood-2017-01-761346

24. Kiyota N, Hasegawa Y, Takahashi S, et al. A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of investigators choice in recurrent squamous cell carcinoma of the head and neck: a subanalysis of Asian patients versus the global population in checkmate 141. Oral Oncol. 2017;73:138146. doi:10.1016/j.oraloncology.2017.07.023

25. Khaddour K, Musiek A, Cornelius LA, et al. Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for szary syndrome. J Immunol Cancer. 2019;7:338. doi:10.1186/s40425-019-0801-z

26. Herbaux C, Gauthier J, Brice P, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed hodgkin lymphoma. Blood. 2017;129:24712478. doi:10.1182/blood-2016-11-749556

27. Peggs KS, Kayani I, Edwards N, et al. Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for hodgkins lymphoma. J Clin Oncol. 2011;29:971978. doi:10.1200/JCO.2010.32.1711

28. Anastasia A, Carlo-Stella C, Corradini P, et al. Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the fondazione Italiana linfomi. Br J Haematol. 2014;166:140142. doi:10.1111/bjh.12821

29. Carlo-Stella C, Ricci F, Dalto S, et al. Brentuximab vedotin in patients with hodgkin lymphoma and a failed allogeneic stem cell transplantation: results from a named patient program at four Italian centers. Oncologist. 2015;20:323328. doi:10.1634/theoncologist.2014-0420

30. Tsirigotis P, Danylesko I, Gkirkas K, et al. Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:13131317. doi:10.1038/bmt.2016.129

31. Angenendt L, Schliemann C, Lutz M, et al. Nivolumab in a patient with refractory Hodgkins lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:443445. doi:10.1038/bmt.2015.266

32. Yared JA, Hardy N, Singh Z, et al. Major clinical response to nivolumab in relapsed/refractory hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:850852. doi:10.1038/bmt.2015.346

33. Onizuka M, Kojima M, Matsui K, et al. Successful treatment with low-dose nivolumab in refractory hodgkin lymphoma after allogeneic stem cell transplantation. Int J Hematol. 2017;106:141145. doi:10.1007/s12185-017-2181-9

34. Shad AT, Huo JS, Darcy C, et al. Tolerance and effectiveness of nivolumab after pediatric T-cell replete, haploidentical, bone marrow transplantation: a case report. Pediatr Blood Cancer. 2017;64. doi:10.1002/pbc.26257

35. Godfrey J, Bishop MR, Syed S, Hyjek E, Kline J. PD-1 blockade induces remissions in relapsed classical hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation. J Immunol Cancer. 2017;5:11. doi:10.1186/s40425-017-0211-z

36. El Cheikh J, Massoud R, Abudalle I, et al. Nivolumab salvage therapy before or after allogeneic stem cell transplantation in hodgkin lymphoma. Bone Marrow Transplant. 2017;52:10741077. doi:10.1038/bmt.2017.69

37. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677704. doi:10.1146/annurev.immunol.26.021607.090331

38. Francisco LM, Sage PT, Sharpe AH, The PD-1. pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219242.

39. Fujiwara H, Maeda Y, Kobayashi K, et al. Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease. J Immunol. 2014;193:25652573. doi:10.4049/jimmunol.1400954

40. Wang AY, Kline J, Stock W, et al. Unexpected toxicities when nivolumab was given as maintenance therapy following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2020;26:10251027. doi:10.1016/j.bbmt.2020.01.021

41. Steinerov K, Jindra P, Lysk D, Karas M. Development of resistant GvHD in a patient treated with nivolumab for hodgkins lymphoma relapse after allogeneic unrelated transplantation. Klin Onkol. 2019;32:6669. doi:10.14735/amko201966

42. Ijaz A, Khan AY, Malik SU, et al. Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol Blood Marrow Transplant. 2019;25:9499. doi:10.1016/j.bbmt.2018.08.028

43. Albring JC, Inselmann S, Sauer T, et al. PD-1 checkpoint blockade in patients with relapsed AML after allogeneic stem cell transplantation. Bone marrow transplantation. 2017. doi:10.1038/bmt.2016.274

44. Covut F, Pinto R, Cooper BW, et al. Nivolumab before and after allogeneic hematopoietic cell transplantation. Bone marrow transplantation. 2017. doi:10.1038/bmt.2017.44

45. Herbaux C, Gauthier J, Brice P, et al. Nivolumab Is Effective and Reasonably Safe in Relapsed or Refractory Hodgkin's Lymphoma after Allogeneic Hematopoietic Cell Transplantation: A Study from the Lysa and SFGM-TC. Blood. 2015. doi:10.1182/blood.V126.23.3979.3979

46. Schoch LK, Borrello I, Fuchs EJ, et al. Checkpoint Inhibitor Therapy and Graft Versus Host Disease in Allogeneic Bone Marrow Transplant Recipients of Haploidentical and Matched Products with Post-Transplant Cyclophosphamide. Blood. 2016. doi:10.1182/blood.V128.22.4571.4571

47. Davids MS, Kim HT, Costello C, et al. Optimizing Checkpoint Blockade As a Treatment for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation. Blood. 2017. doi:10.1182/blood.V130.Suppl_1.275.275

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[Full text] Successful Use of Nivolumab in a Patient with Head and Neck Cancer Aft | OTT - Dove Medical Press

Drugs that trip cellular alarm could help clear out hibernating HIV – New Atlas

HIV can currently be managed with a lifelong daily drug regimen, but unfortunately the infection cant be eliminated entirely. Now, researchers have found a potential way to trip a cellular alarm to alert the immune system to clear out infected cells.

An HIV diagnosis is no longer a death sentence antiretroviral therapy (ART) can prevent the virus from replicating and spreading, letting patients live mostly normal lives. But the virus still lurks inside infected cells, ready to spring into action if the daily drug treatment is ever interrupted.

However, recent work has raised hopes that HIV might be completely curable in the not-too-distant future. Various studies have shown promise in ripping the virus from its hideout using kick and kill drug combos, immunotherapy, engineered stem cells, genetic kill switches, CRISPR gene-editing, or CRISPR and ART drugs together.

In the new study, researchers from Washington University in St. Louis identified a promising new method. They found that human immune cells have an alarm system called the CARD8 inflammasome, which detects a protein called HIV protease and marks the infected cell for destruction.

The problem is, HIV is crafty and it knows how to avoid detection. It silences that protein while inside cells, and usually only activates it once it leaves immune cells, where CARD8 cant reach it.

So for the new study, the researchers found a way to activate that protein while the virus is still inside the cell, where CARD8 can detect it and alert the immune system to destroy the infected cell. Using this method, HIV could be dragged out of hiding and eliminated from a patient entirely. Better yet, one of the drugs that makes HIV protease active again is efavirenz, an antiretroviral drug already in use for HIV.

Weve long used this class of drugs to block HIV from inserting its genetic material into new cells, says Liang Shan, senior author of the study. Thats their day job. But now, we have learned they have a second job activating HIV protease inside the infected cell. When we treat HIV-infected human T cells with this drug, the protease becomes activated before the virus successfully leaves the infected cells. This triggers the CARD8 inflammasome, and the infected cells die within hours. This is a potential route to clearing the virus that we have never been able to completely eliminate.

In tests in human cells in culture, the team showed that the technique worked to destroy the infected cells. It even worked against a range of HIV subtypes found around the world.

Of course, its still early days for the study, and theres no guarantee that the results would carry across to humans. Tests in animals will likely follow, before any trials in humans are conducted, but the method is another intriguing potential tool to add to our growing arsenal against HIV.

The research was published in the journal Science.

Source: Washington University in St. Louis

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Responses to Liso-Cel Not Influenced by Prior Treatment With Anti-CD19 Agents in R/R Large B-Cell Lymphoma – Targeted Oncology

A post-hoc analysis of the practice-changing TRANSCEND NHL 001 trial (NCT02631044) revealed that exposure to anti-CD19 therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL), did not impact response to lisocabtagene maraleucel (liso-cel; Breyanzi).1

Data were presented during the 2021 Transplantation & Cellular Therapy Meeting and showed that among 12 patients who had previously received anti-CD19 therapy, 2 patients achieved a complete response (CR) as their best response to that treatment, 3 patients reported a partial response (PR), and 1 achieved stable disease. Five patients experienced disease progression, while 1 patients response status was unknown.

Results from the analysis showed that 92% (n = 11/12) experienced an objective response to liso-cel per independent review committee (IRC) assessment and Lugano criteria; this included 6 CRs (50%) and 5 PRs with the CAR T-cell therapy. Moreover, 5 patients experienced a duration of response (DOR) to liso-cel of 9 months or longer (range, 0.8-27.4), with 4 patients continuing to respond at the time of data cutoff.

The response rates reported in this subgroup proved to be comparable to those observed in the overall TRANSCEND NHL 001 study population. Of the 256 patients determined to be efficacy evaluable, which included those who were given at least 1 dose of liso-cel and had PET-positive disease per IRC, the objective response rate was 73% (95% CI, 66.8%-78.0%), with a CR rate of 53% (95% CI, 46.8%-59.4%).2 The median DOR had not been reached (95% CI, 8.6not reached [NR]). Moreover, the median progression-free survival (PFS) was 6.8 months in this population (95% CI, 3.3-14.1) and the median overall survival (OS) was 21.1 months (95% CI, 13.3-NR).

In this post-hoc analysis of a small subset of patients from TRANSCEND, patient response to liso-cel and liso-cel pharmacokinetics were not impacted by prior exposure to anti-CD19 therapy, Scott R. Solomon, MD, of the Blood and Marrow Transplant Program, Leukemia and Cellular Immunotherapy Program at the Northside Hospital Cancer Institute, and colleagues, wrote in a poster highlighting the data. Additional analyses on a larger number of patients with prior anti-CD19 therapy are warranted to confirm these findings.

An investigational, CD19-targeted, defined composition, 4-1BB CAR T-cell product, liso-cel is given at equal target doses of CD8 and CD4 T cells; the product has showcased safety and efficacy in patients with aggressive, relapsed/refractory LBCL in the TRANSCEND NHL 001 trial. Data from the trial led to theFebruary 2021 FDA approval of liso-cel for use in adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.

The multicenter, pivotal, phase 1 trial enrolled adult patients aged 18 years or older with relapsed/refractory LBCL; this included those with diffuse large B-cell lymphoma (DLBCL); high-grade B-cell lymphoma with rearrangements of MYC and either BCL-2, BCL-6, or both; DLBCL transformed from an indolent lymphoma; primary mediastinal B-cell lymphoma; and follicular lymphoma. To be eligible for enrollment, patients had to have an ECOG performance status of 0-2, creatinine clearance of greater than 30 mL/min/1.73 m2, and a left ventricular ejection fraction of at least 40%.

Those who underwent prior hematopoietic stem cell transplantation and those with secondary central nervous system lymphoma were permitted. Notably, no lower threshold for absolute lymphocyte count, absolute neutrophil count, platelets, or hemoglobin, were established.

In the trial, patients were screened and then underwent leukapheresis where bridging therapy was permitted while the product was being manufactured. Once disease was reconfirmed via PET imaging, patients went on to receive lymphodepleting chemotherapy with fludarabine at 30 mg/m2 and cytarabine at 300 mg/m2, delivered over the course of 3 days. Two to 7 days after the chemotherapy, patients received liso-cel.

A total of 269 participants were assigned to 1 of 3 target dose levels of the CAR T-cell product: 50 106 CAR T cells (1 or 2 doses), 100 106, and 150 106; this was given as a sequential infusion of 2 components, CD8 and CD4 CAR T cells, at equal target doses.

The co-primary end points of the trial included adverse effects (AEs), dose-limiting toxicities, and ORR per Lugano criteria and IRC. Key secondary end points comprised CR rate by IRC, DOR, PFS, OS, and cellular kinetics.

For the post-hoc analysis, investigators looked at a subset of patients from the trial who had previously received CD19-targeted therapy before liso-cel to evaluate impact of the CAR T-cell product on safety and efficacy outcomes, as well as cellular kinetics.

The median age of the 12 patients in the subgroup of interest was 60.5 years, and 83% were male. Half of the patients had an ECOG performance status of 0, while the remainder had a status of 1. The median number of previous lines of treatment was 4. Fifty-eight percent of patients previously underwent transplantation and 67% were refractory to chemotherapy. Regarding histology, 58% had DLBCL not otherwise specified, 33% had DLBCL that was transformed from follicular lymphoma, and 8% had high-grade B-cell lymphoma.

Additional data showed that previous anti-CD19 therapy did not impact cellular kinetic parameters. Liso-cel demonstrated long-term persistence at 3 months in the majority, or 83% (n = 5/6), of those who received prior CD19-targeted treatment; persistence at 1 year was observed in 50% of patients (n = 2/4), which was comparable to those who did not receive previous CD19-targeted treatment.

Regarding safety, all patients in this subgroup experienced treatment-emergent AEs (TEAEs), 58% (n = 7) of which were grade 3 or higher. The most reported grade 3 or higher TEAEs included neutropenia (58%), thrombocytopenia (42%), and anemia (33%). Sixty-seven percent of patients reported all-grade cytokine release syndrome (CRS) and 42% experienced all-grade neurological effects with liso-cel. However, all toxicity rates proved to be comparable to those experienced by the overall study population and all CRS or neurological effects were either grade 1 or 2.

These findings suggest that liso-cel can be considered for the treatment of patients who have received prior anti-CD19 therapies, concluded Solomon.

References:

1. Solomon S, Mehta A, Abramson JS, et al. Experience of prior anti-CD19 therapy in patients with relapsed or refractory large B-cell lymphoma receiving lisocabtagene maraleucel (liso-cel), an investigational anti-CD19 chimeric antigen receptor T cell product. Presented at: 2021 Transplantation & Cellular Therapy Meeting; February 9-13, 2021; Virtual.

2. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

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Responses to Liso-Cel Not Influenced by Prior Treatment With Anti-CD19 Agents in R/R Large B-Cell Lymphoma - Targeted Oncology