Publications by authors named "Premal D Lulla"

6 Publications

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T-Cell Therapy for Lymphoma Using Nonengineered Multiantigen-Targeted T Cells Is Safe and Produces Durable Clinical Effects.

J Clin Oncol 2021 Jan 28:JCO2002224. Epub 2021 Jan 28.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.

Purpose: Patients with relapsed lymphomas often fail salvage therapies including high-dose chemotherapy and mono-antigen-specific T-cell therapies, highlighting the need for nontoxic, novel treatments. To that end, we clinically tested an autologous T-cell product that targets multiple tumor-associated antigens (TAAs) expressed by lymphomas with the intent of treating disease and preventing immune escape.

Patients And Methods: We expanded polyclonal T cells reactive to five TAAs: PRAME, SSX2, MAGEA4, SURVIVIN, and NY-ESO-1. Products were administered to 32 patients with Hodgkin lymphomas (n = 14) or non-Hodgkin lymphomas (n = 18) in a two-part phase I clinical trial, where the objective of the first phase was to establish the safety of targeting all five TAAs (fixed dose, 0.5 × 10 cells/m) simultaneously and the second stage was to establish the maximum tolerated dose. Patients had received a median of three prior lines of therapy and either were at high risk for relapse (adjuvant arm, n = 17) or had chemorefractory disease (n = 15) at enrollment.

Results: Infusions were safe with no dose-limiting toxicities observed in either the antigen- or dose-escalation phases. Although the maximum tolerated dose was not reached, the maximum tested dose at which efficacy was observed (two infusions, 2 × 10 cells/m) was determined as the recommended phase II dose. Of the patients with chemorefractory lymphomas, two (of seven) with Hodgkin lymphomas and four (of eight) with non-Hodgkin lymphomas achieved durable complete remissions (> 3 years).

Conclusion: T cells targeting five TAAs and administered at doses of up to two infusions of 2 × 10 cells/m are well-tolerated by patients with lymphoma both as adjuvant and to treat chemorefractory lymphoma. Preliminary indicators of antilymphoma activity were seen in the chemorefractory cohort across both antigen- and dose-escalation phases.
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http://dx.doi.org/10.1200/JCO.20.02224DOI Listing
January 2021

The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma.

Sci Transl Med 2020 07;12(554)

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX 77030, USA.

Multiple myeloma (MM) is an almost always incurable malignancy of plasma cells. Despite the advent of new therapies, most patients eventually relapse or become treatment-refractory. Consequently, therapies with nonoverlapping mechanisms of action that are nontoxic and provide long-term benefit to patients with MM are greatly needed. To this end, we clinically tested an autologous multitumor-associated antigen (mTAA)-specific T cell product for the treatment of patients with high-risk, relapsed or refractory MM. In this study, we expanded polyclonal T cells from 23 patients with MM. T cells whose native T cell receptors were reactive toward five myeloma-expressed target TAAs (PRAME, SSX2, MAGEA4, Survivin, and NY-ESO-1) were enriched ex vivo. To date, we have administered escalating doses of these nonengineered mTAA-specific T cells (0.5 × 10 to 2 × 10 cells/m) to 21 patients with MM, 9 of whom were at high risk of relapse after a median of 3 lines of prior therapy and 12 with active, relapsed or refractory disease after a median of 3.5 prior lines. The cells were well tolerated, with only two transient, grade III infusion-related adverse events. Furthermore, patients with active relapsed or refractory myeloma enjoyed a longer than expected progression-free survival and responders included three patients who achieved objective responses concomitant with detection of functional TAA-reactive T cell clonotypes derived from the infused mTAA product.
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http://dx.doi.org/10.1126/scitranslmed.aaz3339DOI Listing
July 2020

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

Adoptive Cell Therapy for Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia.

Cancer J 2019 May/Jun;25(3):199-207

From the Center for Cell and Gene Therapy at Baylor College of Medicine; Houston Methodist Hospital; and Texas Children's Hospital, Houston, Texas.

Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are emerging as an effective treatment for patients with chemotherapy refractory hematological malignancies. Indeed, the use of unselected donor lymphocyte infusions has demonstrated successes in treating patients with AML and T-lineage leukemia post-allogeneic transplantation. The development of ex vivo manipulation techniques such as genetic modification or selection and expansion of individual cellular components has permitted the clinical translation of a wide range of promising cellular therapies for AML and T-cell acute lymphoblastic leukemia. Here, we will review clinical studies to date using adoptive cell therapy approaches and outline the major challenges limiting the development of safe and effective cell therapies for both types of acute leukemia.
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http://dx.doi.org/10.1097/PPO.0000000000000376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602906PMC
July 2020

The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma.

Clin Adv Hematol Oncol 2018 May;16(5):375-386

Baylor College of Medicine, Houston, Texas.

Resistance to conventional lines of therapy develops in approximately 20% of all patients with lymphoma. These patients have a dismal prognosis, with an expected median survival of 6.3 months. In recent years, T-cell immunotherapy has demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphoma. A major contributor to the success of immunotherapy has been the advent of genetic engineering technologies that introduce a chimeric antigen receptor (CAR) into T cells to focus their killing activity on tumor cells. The adoptive transfer of autologous CAR T-cell products specific for the pan-B-cell antigen CD19 have now received approval from the US Food and Drug Administration (FDA) for the treatment of relapsed or chemotherapy-resistant B-cell non-Hodgkin lymphoma. This review is designed to showcase the clinical efficacy and unique toxicities of individually developed CAR T-cell products for the treatment of lymphomas and their evolution from the laboratory bench to commercialization.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469642PMC
May 2018

Sustained complete remission of metastatic hepatocellular carcinoma with single agent sorafenib.

J Gastrointest Cancer 2013 Mar;44(1):98-101

Department of Medicine, Baylor College of Medicine, 1709 Dryden Road, Houston, TX 77004, USA.

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http://dx.doi.org/10.1007/s12029-012-9438-6DOI Listing
March 2013