Publications by authors named "Natalie S Grover"

11 Publications

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Extending the Promise of Chimeric Antigen Receptor T-Cell Therapy Beyond Targeting CD19 Tumors.

J Clin Oncol 2021 Feb 12;39(5):499-513. Epub 2021 Jan 12.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC.

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http://dx.doi.org/10.1200/JCO.20.01738DOI Listing
February 2021

Consolidative or palliative whole brain radiation for secondary CNS diffuse large B-Cell lymphoma.

Leuk Lymphoma 2021 01 16;62(1):68-75. Epub 2020 Sep 16.

Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, NC, USA.

We analyzed 25 patients receiving whole brain radiation (WBRT) for secondary CNS lymphoma (SCNSL), grouped by consolidative intent (after complete/partial response,  = 13) vs. palliative intent (initial CNS treatment, primary refractory disease, or CNS progression,  = 12). Median WBRT dose for the consolidative and palliative cohorts were 24 Gy and 30 Gy, respectively. For 13 patients receiving consolidative WBRT, median OS was 24 months from WBRT and 2-year OS was 64%. Three patients had CNS relapse at 2, 9, and 24 months after consolidative WBRT. For 12 patients receiving palliative WBRT, median OS was 3 months from WBRT and two-year OS was 8%. All 10 patients with neurologic symptoms had documented improvement. In conclusion, consolidative WBRT after chemotherapy response led to reasonable long-term survival and may be an effective strategy for SCNSL, especially transplant-ineligible patients and/or isolated CNS recurrence. Palliative WBRT effectively improved neurologic symptoms, but survival was usually only months.
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http://dx.doi.org/10.1080/10428194.2020.1821014DOI Listing
January 2021

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma.

J Clin Oncol 2020 11 23;38(32):3794-3804. Epub 2020 Jul 23.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL).

Methods: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.

Results: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.

Conclusion: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
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http://dx.doi.org/10.1200/JCO.20.01342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655020PMC
November 2020

Clinicopathologic correlates of L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma.

Leuk Lymphoma 2019 12 11;60(12):2880-2889. Epub 2019 Jun 11.

Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Primary central nervous system lymphoma (PCNSL) patients have a poorer prognosis than systemic lymphoma. Gain-of-function c.794T > C (p. L265P) mutation and programed cell death-1 (PD-1) pathway alterations are potential targetable pathways. Our study objective was to determine the clinicopathologic correlates of mutation and PD-1 alterations in PCNSL and the impact of Epstein-Barr virus (EBV) infection. We studied 53 cases including 13 EBV-associated (EBV) PCNSL, 49% harbored mutation, none seen in EBV PCNSL. MYD88 protein expression did not correlate with mutation. T-cell and macrophage infiltration was common. All PD-L1-positive tumors were EBV. Two PD-L1 positive tumors showed 9p24.1/PD-L1 locus alterations by Fluorescence Hybridization. T cells and macrophages expressed PD-1 and/or PD-L1 in 98% and 83% cases, respectively. mutation or protein expression and PD-1 or PD-L1 expression did not predict outcome. We hypothesize that EBV PCNSL has a distinct activation mechanism, independent of genetic alterations.
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http://dx.doi.org/10.1080/10428194.2019.1620942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280020PMC
December 2019

Challenges of driving CD30-directed CAR-T cells to the clinic.

BMC Cancer 2019 Mar 6;19(1):203. Epub 2019 Mar 6.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.

Chimeric antigen receptor T (CAR-T) cells are a promising new treatment for patients with relapsed or refractory hematologic malignancies, including lymphoma. Given the success of CAR-T cells directed against CD19, new targets are being developed and tested, since not all lymphomas express CD19. CD30 is promising target as it is universally expressed in virtually all classical Hodgkin lymphomas, anaplastic large cell lymphomas, and in a proportion of other lymphoma types, including cutaneous T cell lymphomas and diffuse large B cell lymphomas. Preclinical studies with CD30-directed CAR-T cells support the feasibility of this approach. Recently, two clinical trials of CD30-directed CAR-T cells in relapsed/refractory CD30+ lymphomas, including Hodgkin lymphoma, have been reported with minimal toxicities noted and preliminary efficacy seen in a proportion of patients. However, improving the persistence and expansion of CAR-T cells is key to further enhancing the efficacy of this treatment approach. Future directions include optimizing the lymphodepletion regimen, enhancing migration to the tumor site, and combination with other immune regulators. Several ongoing and upcoming clinical trials of CD30-directed CAR-T cells are expected to further enhance this approach to treat patients with relapsed and refractory CD30+ lymphomas.
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http://dx.doi.org/10.1186/s12885-019-5415-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404322PMC
March 2019

Hodgkin Lymphoma With Multiple Autoimmune Disorders: Case Report and Review of the Literature.

Clin Lymphoma Myeloma Leuk 2018 09 15;18(9):e365-e368. Epub 2018 Jun 15.

Levine Cancer Institute, Charlotte, NC.

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http://dx.doi.org/10.1016/j.clml.2018.06.009DOI Listing
September 2018

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy.

Cancer 2018 06 26;124(11):2306-2315. Epub 2018 Mar 26.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.

Background: Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy.

Methods: The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL.

Results: A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P<.01) and progression-free survival (PFS) (1.9 vs 4.4 years; P<.01). In patients who underwent high-intensity induction followed by autologous stem cell transplantation (ASCT) in first remission, a CK was associated with poor OS (5.1 vs 11.6 years; P = .04) and PFS (3.6 vs 7.8 years; P<.01). Among patients with a CK, high-intensity induction had no effect on OS (4.5 vs 3.8 years; P = .77) nor PFS (2.3 vs 1.5 years; P = .46). Similarly, ASCT in first remission did not improve PFS (3.5 vs 1.2 years; P = .12) nor OS (5.1 vs 4.0 years; P = .27). On multivariable analyses with Ki-67 and MIPI, only CK was found to be predictive of OS (hazard ratio [HR], 1.98; 95% confidence interval [95% CI], 1.12-3.49 [P = .02]), whereas both CK (HR, 1.91; 95% CI, 1.17-3.12 [P = .01]) and Ki-67 >30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival.

Conclusions: CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992038PMC
June 2018

Targeting Immune System Alterations in Hodgkin Lymphoma.

Curr Hematol Malig Rep 2017 08;12(4):358-369

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27516, USA.

Purpose Of Review: This review discusses novel immunotherapeutic approaches to treat Hodgkin lymphoma (HL), specifically PD-1 inhibitors and cellular immunotherapy.

Recent Findings: PD-1 inhibitors have shown promising results in the treatment of relapsed or refractory HL, leading to FDA approval of nivolumab and pembrolizumab, although complete remissions are rare. Chimeric antigen receptor T cells directed against CD30 have been investigated with preliminary clinical trials showing minimal toxicities and some responses in heavily pre-treated patients with HL. HL is unique as it consists of a small percentage of malignant cells (Hodgkin Reed Sternberg cells) surrounded by an inflammatory microenvironment which promotes tumor growth and suppresses immune responses, making it an ideal target for immunotherapeutic approaches, such as PD-1 inhibitors and cellular immunotherapy. Current research is focused on overcoming barriers to efficacy via rational combinations that overcome resistance to therapy.
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http://dx.doi.org/10.1007/s11899-017-0398-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593851PMC
August 2017

A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma.

Br J Haematol 2016 Oct 22;175(2):281-289. Epub 2016 Jul 22.

Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA.

Bendamustine in combination with rituximab (BR) has been associated with high response rates and acceptable toxicity in older patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Evaluation of BR is warranted in the front-line setting for DLBCL patients not eligible for anthracyclines or for the elderly. In this phase II study, we enrolled DLBCL patients aged ≥65 years who were poor candidates for R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to determine the efficacy and safety of BR in previously untreated stage II-IV DLBCL. Twenty-three patients were enrolled with a median age of 80 years. 52% of patients presented with poor functional status (Eastern Cooperative Oncology Group performance score of ≥2). The overall response rate was 78% with 12 complete responses (52%). At a median follow up of 29 months, the median overall survival was 10·2 months and the median progression-free survival was 5·4 months. The most common grade 3/4 adverse events were haematological. Combination therapy with BR demonstrates high response rates as front-line therapy in frail older patients with DLBCL, but survival rates were low. BR should be used with caution in future clinical trials involving older DLBCL patients with poor functional status.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063684PMC
http://dx.doi.org/10.1111/bjh.14232DOI Listing
October 2016

Young Men With Cancer Experience Low Referral Rates for Fertility Counseling and Sperm Banking.

J Oncol Pract 2016 05 26;12(5):465-71. Epub 2016 Apr 26.

University of North Carolina, Chapel Hill, NC

Purpose: With improved cancer survival rates and the current trend of delaying parenthood, fertility is a growing issue among cancer patients. The purpose of this study was to evaluate the incidence of fertility counseling and sperm banking in reproductive-age male cancer patients and to assess factors that influence counseling and banking.

Materials And Methods: Male patients ages 13 to 50 years who received a new cancer diagnosis from January 1, 2013, to May 1, 2015, and planned to initiate curative chemotherapy at our center were identified. Documentation of fertility counseling and sperm cryopreservation was abstracted from the medical record. Univariable and multivariable logistic regression modeling was used to examine variables associated with fertility counseling and sperm banking.

Results: Of 201 patients who fit the study criteria, 59 (29%) received fertility counseling and 23 (11%) attempted sperm banking. All patients who banked sperm had documentation of fertility counseling. Younger patients were significantly more likely to be counseled, with mean ages of 27.4 and 40.4 years for counseled and noncounseled patients, respectively (P < .001). Among counseled patients, those with a lower median income (P = .038) or who had Medicaid or no insurance (P = .042) were less likely to bank sperm. In a multivariable logistic regression model, older age (5-year odds ratio, 0.61; P < .001) and presence of comorbidities (odds ratio, 0.15; P = .03) remained significantly associated with a lower counseling rate.

Conclusion: There is a low rate of fertility counseling and referral for sperm banking in young men with cancer receiving chemotherapy. Further work is needed to develop interventions to improve fertility counseling rates and opportunities for sperm banking.
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http://dx.doi.org/10.1200/JOP.2015.010579DOI Listing
May 2016

Novel Targeted Agents in Hodgkin and Non-Hodgkin Lymphoma Therapy.

Pharmaceuticals (Basel) 2015 Sep 17;8(3):607-36. Epub 2015 Sep 17.

Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA.

There has been a recent emergence of novel targeted agents for treatment of Hodgkin and non-Hodgkin lymphoma. In particular, antibodies and antibody-drug conjugates directed against surface antigens, agents that block immune checkpoint pathways, and small molecule inhibitors directed against cell signaling pathways have shown significant promise in patients with relapsed and refractory disease and in the frontline setting. With the development of these new therapies, cytotoxic chemotherapy may be avoided entirely in some clinical settings. This review will present the latest information on these novel treatments in Hodgkin and non-Hodgkin lymphoma and will discuss both recently approved agents as well as drugs currently being studied in clinical trials.
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http://dx.doi.org/10.3390/ph8030607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588185PMC
September 2015