Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II–Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3

Abstract

Purpose

Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I–restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8⁺ T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4⁺ T-cell therapy using an MHC class II–restricted, HLA-DPB1*0401–restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3).

Patients and Methods

Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4⁺ T cells, retrovirally transduced with MAGE-A3 TCR plus systemic high-dose IL-2. A cell dose escalation was conducted, starting at 10⁷ total cells and escalating at half-log increments to approximately 10¹¹ cells. Nine patients were treated at the highest dose level (0.78 to 1.23 × 10¹¹ cells).

Results

Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 × 10⁹ cells (ongoing at ≥ 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at ≥ 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths.

Conclusion

These results demonstrate the safety and efficacy of administering autologous CD4⁺ T cells that are genetically engineered to express an MHC class II–restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer.

INTRODUCTION

Adoptive cell transfer (ACT) is a personalized cancer immunotherapy that involves the administration of a patient’s own autologous immune cells.¹ Transferred T cells can be genetically modified with a T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to redirect them to attack the tumor. Administration of CAR-modified T cells that target B-cell lineage differentiation antigen CD19 can lead to objective responses in patients with B-cell cancers^2-11; however, thus far, it has been challenging to extend CAR T-cell therapy to patients with solid tumors. In large part, this has been because solid cancers generally lack suitable cell-surface targets that only express on tumor cells but not on normal cells. Recognition of normal tissues by CAR T cells can potentially trigger unacceptable toxicities.¹²

In contrast to CARs, TCRs are capable of recognizing antigens that are derived from intracellular proteins. Most current TCR therapies use major histocompatibility complex (MHC) class I–restricted TCRs to genetically modify CD8⁺ T cells or bulk T cells for patient treatment; however, some evidence has suggested that CD4⁺ T cells alone could induce tumor regressions. In mice, established B16 melanoma could be eradicated by tumor-specific CD4⁺ T cells, whose activities could be further enhanced by either cytotoxic T-cell lymphocyte-4 blockade, OX40 stimulation, or Th17 polarization.^13-15 In humans, a durable clinical response was observed in a patient with metastatic melanoma who was treated with an autologous HLA-DP4–restricted NY-ESO-1–specific CD4⁺ T-cell clone, as well as in a patient with metastatic cholangiocarcinoma who was treated with mutated ERBB2IP-reactive CD4⁺ T cells that were grown from tumor-infiltrating lymphocytes.^16,17 These clinical studies indicate that transferring CD4⁺ T cells can induce long-term tumor regression in humans.

Cancer germline (CG) antigens, a class of tumor-associated antigens, show limited expression in normal adult tissues, except for germline-derived tissues. Of importance, germ cells lack expression of MHC molecules and are therefore protected from T cell–mediated immune surveillance. Conversely, CG antigens can show high levels of expression in a variety of cancer types.^18,19 Among these antigens, MAGE-A3 (melanoma-associated antigen-A3) is the most frequently expressed CG antigen in a variety of cancer types and has been targeted by cancer immunotherapies, including ACT therapies.^20-31 In a previous preclinical study, an MHC class II–restricted, HLA-DPB1*0401–restricted TCR that recognized MAGE-A3/A6 was isolated from the peripheral blood of a patient who received a MAGE-A3 peptide vaccine.³² The human constant regions of TCRα/β chains were replaced by mouse constant regions to enhance TCR pairing and reactivity.³³ This TCR was demonstrated to recognize MAGE-A3 and its closest family member, MAGE-A6, which has 95.9% homology with MAGE-A3. Expression of MAGE-A3 and MAGE-A6 was not observed in any normal tissues, except testes.³⁴ A clinical trial was thus designed and conducted to test whether ACT that used genetically modified CD4⁺ T cells targeting MAGE-A3 could induce tumor regression in patients with a variety of metastatic solid cancers. Previous animal studies indicated that IL-2 administration could significantly enhance T cell–mediated antitumor activity. As a result, our previous ACT clinical trials included high-dose IL-2 therapy; therefore, this clinical trial was designed to incorporate high-dose IL-2 therapy in patients after cell infusion.^35-38

PATIENTS AND METHODS

Study Design

This clinical trial was designed to determine the maximum safe dose of the administration of autologous CD4⁺ cells that were retrovirally transduced with an HLA-DPB*0401–restricted MAGE-A3 TCR and whether this approach could result in clinical tumor regression in patients with metastatic cancer.

Before therapy, peripheral blood lymphocytes (PBLs) were isolated from patients by leukapheresis and separated by centrifugation on a lymphocyte separation medium cushion. CD8⁺ lymphocytes were labeled with clinical-grade CD8 antibody–coated magnetic particles, then depleted by using a CliniMACS clinical-scale cell separation apparatus (Miltenyi Biotec, Bergisch Gladbach, Germany). CD8⁺ T cell–depleted PBLs were stimulated by OKT3 antibody (50 ng/mL) and transduced with a γ-retroviral vector that encodes the HLA-DPB*0401–restricted MAGE-A3 TCR, as previously described.³² National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules were followed. In the final cell products that were used for patient treatment, the median percentage of CD4⁺ T cells was 99% (range, 94% to 100%), and the median percentage of transduced CD4⁺ T cells was 90% (range, 77% to 92%).

Patients were treated with a nonmyeloablative chemotherapy preparative regimen (cyclophosphamide 60 mg/kg per day for 2 days and fludarabine 25 mg/m² per day for 5 days), followed by a single intravenous infusion of autologous TCR-transduced CD4⁺ T cells. A cell dose escalation was conducted, treating one patient in each cohort, starting at 10⁷ total cells and escalating at half-log increments. Nine patients were treated at the highest dose level (approximately 10¹¹ cells). After cell infusion, patients received high-dose IL-2 intravenously at 720,000 IU/kg every 8 hours to physiologic tolerance.

Patients

Patients 18 to 70 years of age with a pathologically confirmed diagnosis of metastatic or locally advanced refractory/recurrent cancer were eligible for this clinical trial. All patients had progressive disease after at least one standard first-line therapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, to be eligible, patients must be HLA-DPB1*0401 positive and with tumors that contained > 50% MAGE-A–positive tumor cells. Immunohistochemistry of tumor specimens was performed and scored by the Laboratory of Pathology at the National Cancer Institute using an anti–MAGE-A antibody (6C1; Santa Cruz Biotechnologies, Santa Cruz, CA).³⁴ Responses of patients to therapy were assessed by using Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) guidelines and evaluated starting 1 month after cell administration and proceeding at regular intervals thereafter.

Immunologic Assay

Serum samples were obtained daily from patients during hospitalization. To determine the cytokine concentrations in serum samples, enzyme-linked immunosorbent assay for interferon gamma (IFN-γ), IL-6, IL-10, and TNF were performed according to manufacturer instructions (Thermo Fisher Scientific Life Sciences, Waltham, MA; and R&D Systems, Bio-Techne Corp, Minneapolis, MN). Before therapy and approximately 1 month after therapy, PBLs were isolated from patients by leukapheresis for flow cytometric analyses. Patients 7, 13, 14, and 17 did not undergo leukapheresis after therapy, rather, patients’ peripheral blood was collected into Vacutainer Cell Preparation Tubes (CPTs) (BD Bioscience, San Jose, CA), then tubes were spun down to isolate patients’ lymphocytes according to manufacturer instruction. PBL samples from patient 4 were unavailable. Anti-FOXP3 (236A/E7) and mouse anti-TCRβ (H57-597) antibodies were obtained from Thermo Fisher Scientific Life Sciences. Fixation/permeabilization and staining were performed according to manufacturer instructions (Thermo Fisher Scientific Life Sciences). Flow cytometric analyses were performed by using FACSCanto (BD Bioscience) and analyzed with FlowJo software (FlowJo, Ashland, OR).

Statistical Analysis

Mann-Whitney U test was used to test for correlations between T-cell persistence and cell doses (Prism; GraphPad Software, La Jolla, CA). Reported P values were two-tailed, and P < .05 were considered statistically significant.

RESULTS

Patient Characteristics

Seventeen patients with metastatic cancer were treated with TCR-transduced CD4⁺ T cells in this protocol (Table 1). One additional patient with metastatic bladder cancer did not receive any T cells or IL-2 as a result of toxicities after two doses of cyclophosphamide and two doses of fludarabine. All patients had measurable distant metastatic disease and had been previously treated with at least one standard first-line therapy. Because no unexpected dose-limiting toxicities—grade 3 and 4—were observed during the cell dose-escalation phase (dose cohort 1 to 8), the last nine patients (patient 9 to 17) were treated at the highest dose level (dose cohort 9). The median cell dose for dose cohort 9 was 1.00 × 10¹¹ T cells (range, 0.6 to 1.23 × 10¹¹ T cells). Because of the patient’s poor pulmonary function, patient 15 received a split dose of T cells with 3 × 10¹⁰ cells on day 0, then 3 × 10¹⁰ cells the next day. After cell infusion, patients also received high-dose IL-2, with the exception of three patients who had poor pulmonary function. Most patients were discharged after their whole blood cell counts were back to normal range. Because most patients were not local to the National Institutes of Health, they were hospitalized for the entire chemotherapy. Most patients were hospitalized for 13 days after cell infusion (range, 10 to 40 days).

Table 1.

Patient Characteristics, Therapies, and Responses

Clinical Responses

Eight patients were treated during the cell dose-escalation phase (low dose). Patient 6 with cervical cancer had been treated with radiation therapy and six cycles of cisplatin for primary cervical cancer and lymph node metastases; however, the patient later developed disease progression in the supraclavicular lymph nodes, which were positron emission tomography positive and biopsy proven to be recurrent cancer. The patient received 2.7 × 10⁹ TCR-transduced CD4⁺ T cells and subsequently experienced an objective complete response in metastatic supraclavicular lymph nodes that is ongoing at 29 months (Fig 1A). Her remaining lymph node was positron emission tomography negative and less than 1 cm.

Fig 1.

Clinical responses of patients 6, 11, and 16. (A) Computed tomography (CT) scans of the neck of patient 6 with metastatic cervical cancer before (left) and 29 months after (right) T-cell therapy. (B) Magnetic resonance imaging scans of patient 11 with metastatic urothelial cancer before (left) and 18 months after (right) T-cell therapy. (C) CT scans of the chest of patient 16 with metastatic osteosarcoma before (left) and approximately 4 months after (right) T-cell therapy. Arrows indicate the locations of metastatic lesions before and after therapy.

Among nine patients who received the highest dose level of TCR-transduced CD4⁺ T cells (high dose), three patients experienced objective responses. Patient 9 with esophageal cancer was previously treated with radiation, FOLFOX (folinic acid-fluororuracil-oxaliplatin), and capecitabine. The patient experienced an objective partial response in mediastinal and paraesophageal lymph nodes, but experienced disease progression at 4 months with a new parasternal lesion (Appendix Fig A1, online only). Patient 11 with urothelial cancer had a primary tumor that involved his left ureter with metastases to the liver and intra-abdominal lymph nodes. The patient experienced disease progression through surgery and chemotherapy before T-cell therapy. ACT treatment resulted in an objective partial response that is ongoing for 19 months, with small residual disease in the periaortic lymph node and liver (Fig 1B). Lastly, Patient 16 with osteosarcoma was heavily pretreated, including surgery, chemotherapy, L-MTP-PE (liposomal muramyl tripeptide phosphatidyl ethanolamine), sorafenib, and radiation therapy. The patient experienced an objective partial response of metastatic lung lesions that lasted 4 months, at which time the growth of nontarget pulmonary lesions was observed (Fig 1C).

Adverse Events

All patients experienced the expected transient grade 3 and 4 adverse events that resulted from nonmyeloablative chemotherapy preparative regimen and high-dose IL-2. Of note, 10 of 17 treated patients experienced prolonged high fever (> 39.0°C to 40.0°C, grade 2) after cell infusion (Appendix Table A1, online only). A 65-year-old patient with metastatic breast cancer received the nonmyeloablatve chemotherapy preparative regimen, 9 × 10¹⁰ cells, and one dose of IL-2. After therapy, the patient experienced grade 4 toxicities, including elevated ALT, AST, and creatinine. The patient subsequently developed respiratory failure and was hospitalized for more than 1 month before recovering. One additional patient experienced transient grade 3 toxicities in elevated ALT, AST, and creatinine that lasted 2 days.

Elevated Serum Cytokine Levels After Cell Infusion

Patients’ serum samples were collected during hospitalization, and serum cytokine concentrations of IL-6, IL-10, IFN-γ, and TNF were determined by using enzyme-linked immunosorbent assay. Elevated serum cytokines levels were detected 1 to 2 days after cell infusion (Appendix Fig A2, online only). Maximum cytokine levels are summarized in Fig 2. High levels of IL-6 were detected in all patients (range, 491 pg/mL to 9,686 pg/mL), and elevated IL-10 levels (> 100 pg/mL) were detected in 12 of 17 patients. In addition, elevated IFN-γ and TNF levels (> 100 pg/mL) were detected in nine patients and three patients, respectively. Of note, high levels of IFN-γ were detected in three patients (range, 4,898 pg/mL to 12,911 pg/mL); however, the levels of serum cytokines did not seem to correlate with clinical responses or symptoms, such as fevers.

Fig 2.

Elevated serum cytokine levels after adoptive transfer of MAGE-A3 (melanoma-associated antigen-A3) T-cell receptor–transduced CD4⁺ T cells. Serum samples were collected daily during hospitalization. Maximum serum cytokine levels and the corresponding time point after cell infusion are shown. Day 0 is the cell infusion day. Patients with objective responses are labeled in yellow. Low dose: 0.001 to 3 × 10¹⁰ total cells. High dose: Approximately 10¹¹ total cells. n.d., not detectable. **Patients 5 and 8 had elevated interferon gamma (IFN-γ) levels before cell infusion (approximately 500 pg/mL and 4,000 pg/mL, respectively), and IFN-γ levels remained at similar levels after cell infusion.

Persistence of Genetically Modified T Cells in Peripheral Blood

Patients’ PBLs were collected approximately 1 month after cell infusion, and the frequency of TCR-transduced T cells was detected by antibody against the mouse TCRβ constant region. As shown in Figure 3, both the percentage and total number of TCR-transduced T cells were significantly higher in peripheral blood of patients who received the high cell dose compared with patients who received the low cell dose (P = .0002 and .0007, respectively; Figs 3B and 3C). In this small study, no relationship was observed between cell persistence and clinical response. Of note, both patient 9 and patient 16 experienced short-term clinical responses for 4 months. Infused genetically modified T cells still persisted well in the peripheral blood at the time of progression (223 cells/μL [20.1%] and 73 cells/μL [14.4%], respectively). These results suggest that tumors in patient 9 and patient 16 might have developed resistance to this T-cell therapy, such as loss of antigens or dysfunction of components in the antigen process and presentation pathways.

Fig 3.

After cell infusion, T-cell receptor (TCR)–transduced T cells persisted better in the high-dose group compared with the low-dose group. (A) Peripheral blood lymphocyte (PBL) samples before (top) and approximately 1 month after (bottom) T-cell therapy were stained with anti-mouse TCRβ constant region antibody (mTCRβ) to detect MAGE-A3 (melanoma-associated antigen-A3) TCR-transduced T cells. A representative result is shown. (B) Percentage of CD4⁺mTCRβ⁺ cells in lymphocyte populations at approximately 1 month in the low-dose and high-dose patients. (C) Cell numbers of CD4⁺mTCRβ⁺ cells in patients’ peripheral blood. The post-treatment PBL sample from patient 4 was not available. Statistical significance was determined by Mann-Whitney U test. Patients who experienced objective responses are labeled with gray circles. CR, complete response; PR, partial response.

DISCUSSION

Immune checkpoint blockade therapies can induce objective responses in a subset of patients with melanoma, renal cell carcinoma, non–small-cell lung cancer, and urothelial cancer, as well as tumors with mismatch-repair deficiency^39-49; however, to date, these immunotherapies have had little impact in patients with other types of solid cancer. One alternative immunotherapy approach is the adoptive transfer of CAR or TCR-modified T cells; however, previous T-cell therapies targeting MAGE-A3 have failed. A clinical trial that used an HLA-A*01–restricted, affinity-enhanced TCR targeting MAGE-A3 led to lethal toxicity because of the recognition of a muscle protein, TTN (titin), in the heart by the altered TCR.^50,51 In a different trial, ACT of T cells that were genetically engineered to express an HLA-A*0201–restricted TCR targeting MAGE-A3/9 recognized an HLA-A*0201–restricted MAGE-A12 epitope expressed in brain and led to lethal neurologic toxicity.³⁴

In prior studies, cell transfer using cells that were engineered to express HLA-A*0201–restricted NY-ESO-1 TCR mediated a 55% objective response rate for patients with melanoma and a 61% objective response rate for patients with synovial sarcoma.^52,53 In a recent study, the protein expression of MAGE-A and NY-ESO-1 in 3,668 tumor specimens was assessed by immunohistochemistry. The frequency of MAGE-A–positive tumor specimens was significantly higher than NY-ESO-1 in several common epithelial carcinomas, including cutaneous squamous cell carcinomas (SCCs; 52.8% v 2.8%), esophageal SCC (50% v 0%), head and neck SCC (41.1% v 0.65%), bladder urothelial cancer (40.4% v 8.3%), and cervical/anal SCC (37.5% v 0%).³¹ In addition, HLA-DPB1*0401 is present in 57% of the Caucasian population compared with a 47% incidence of HLA-A*0201.⁵⁴ Thus, MAGE-A3 TCR immunotherapy described here could potentially be applicable for additional patients with solid cancers.

Our study provides direct evidence that objective tumor regressions can be mediated by MAGE-A3–specific CD4⁺ T cells in a variety of cancer types; however, additional studies are needed to understand the detailed mechanisms by which human CD4⁺ T cells mediate tumor regressions. Previous studies in the B16 melanoma mouse model suggested that tumor regressions were dependent on IFN-γ secreted by CD4⁺ T cells, as well as MHC class II molecules expressed on B16 melanoma after in vivo IFN-γ stimulation.^13,15 Tumor regressions in mice were not dependent on endogenous CD8⁺ T cells, B cells, NK cells, or NK T cells.^15,55 Thus, MAGE-A3–specific CD4⁺ T cells could possibly recognize tumor cells directly in vivo and kill tumor cells via IFN-γ or other pathways. Alternatively, MAGE-A3–specific CD4⁺ T cells might recognize MAGE-A3 cross-presented by antigen-presenting cells and secrete therapeutic cytokines or promote CD8⁺ T cell–mediated tumor regression by epitope spreading.⁵⁶

The MAGE-A3 TCR used in this study was originally isolated from a T-cell clone with a regulatory T-cell (Treg) phenotype. In addition to being a naturally occurring and thymically selected TCR, this TCR was selected for clinical development because it had a higher affinity compared with another TCR that was isolated from an effector T-cell clone.³² This raised a potential possibility that genetically modified CD4⁺ T cells might convert to Tregs after adoptive transfer of CD4⁺ T cells into patients, and that Tregs might subsequently inhibit T-cell activity in vivo. Furthermore, previous studies in mice have suggested that high-affinity TCRs promoted the differentiation of both thymus-derived and peripherally derived Tregs.⁵⁷ Despite these concerns, we were unable to detect any significant mTCR⁺FOXP3⁺ T cells in any patient’s peripheral blood 1 month after cell infusion, which suggested that transduced T cells did not convert to Tregs (Appendix Fig A3, online only). Data presented here suggested that other factors, such as the context of the tissue microenvironment, might play important roles in the conversion of Tregs.

In conclusion, this study demonstrated the safety of the adoptive transfer of genetically engineered CD4⁺ T cells targeting MAGE-A3 and demonstrated evidence of efficacy. Future clinical trials are needed to study the efficacy of this therapy in different types of cancer. Additional modifications may help to improve the efficacy of this therapy, such as manufacturing less-differentiated or Th17-polarized T cells by modifying the cell production process, and combining T-cell therapy with immune checkpoint blockade to prevent T-cell exhaustion.^11,13,58,59 Combining multiple targets, such as neoantigen targets, at the same time may help overcome the challenge of tumor heterogeneity.^60,61 Finally, clinical studies have demonstrated that tumors can also escape T cell–based immunotherapies by the loss of critical processing and presentation components of MHC class I, such as the deletion of β2-microglobulin. The ability to transfer MHC class II–restricted tumor-reactive T cells may be an effective way to prevent this demonstrated mechanism of tumor escape.⁶²

Appendix

Fig A1.

Computed tomography scans of patient 9 with metastatic esophageal cancer before and 4 months after T-cell therapy.

Fig A2.

Serum cytokine levels before and after cell infusion. Patients 5 and 8 had elevated interferon gamma (IFN-γ) levels before cell infusion (approximately 500 pg/mL and 4,000 pg/mL, respectively), and the IFN-γ levels remained at similar levels after cell infusion (data not shown). CR, complete response; PR, partial response.

Fig A3.

MAGE-A3 (melanoma-associated antigen-A3) T-cell receptor (TCR)–transduced CD4⁺ T cells did not convert to regulatory T cells after cell infusion. (A) Intracellular staining for FOXP3 antibody was performed for peripheral blood lymphocyte samples before (top) and approximately 1 month after (bottom) T-cell therapy. (B) Percentage of CD4⁺mTCRβ⁺FOXP3⁺ cells in lymphocyte populations before (top) and 1 month after (bottom) cell infusion. (C) Percentage of CD4⁺mTCRβ⁻FOXP3⁺ cells in lymphocyte populations before (top) and 1 month after (bottom) cell infusion. Statistical significance was determined by Mann-Whitney U test.

Table A1.

Unexpected Adverse Events

AUTHOR CONTRIBUTIONS

Conception and design: Yong-Chen Lu, Xin Yao, Paul F. Robbins, Steven A. Feldman, Pierre van der Bruggen, James C. Yang, Steven A. Rosenberg

Provision of study materials or patients: Steven A. Feldman, Pierre van der Bruggen

Collection and assembly of data: Yong-Chen Lu, Linda L. Parker, Tangying Lu, Zhili Zheng, Mary Ann Toomey, Donald E. White, Yong F. Li, Christopher A. Klebanoff, Stephanie L. Goff, Richard M. Sherry, Udai S. Kammula, James C. Yang

Data analysis and interpretation: Yong-Chen Lu, Linda L. Parker, Zhili Zheng, Mary Ann Toomey, Yong F. Li, Steven A. Feldman, Christopher A. Klebanoff, Stephanie L. Goff, Richard M. Sherry, Udai S. Kammula, James C. Yang, Steven A. Rosenberg

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II–Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Yong-Chen Lu

Patents, Royalties, Other Intellectual Property: Patents pending, held by the National Cancer Institute (Inst)

Linda L. Parker

No relationship to disclose

Tangying Lu

No relationship to disclose

Zhili Zheng

No relationship to disclose

Mary Ann Toomey

No relationship to disclose

Donald E. White

No relationship to disclose

Xin Yao

Employment: Cellular Biomedicine Group

Stock or Other Ownership: Cellular Biomedicine Group

Yong F. Li

No relationship to disclose

Paul F. Robbins

Patents, Royalties, Other Intellectual Property: Kite Pharma (Inst)

Steven A. Feldman

Patents, Royalties, Other Intellectual Property: Patents: Isolation of MAGE-A3 specific TCRs (commercial license from National Institutes of Health Office of Technology Transfer (OTT)); manufacture of CAR T cells (commercial license from National Institutes of Health OTT by KITE Pharma)

Pierre van der Bruggen

Research Funding: ITeos Therapeutics (Inst)

Patents, Royalties, Other Intellectual Property: Ludwig Cancer Research

Christopher A. Klebanoff

Stock or Other Ownership: Kite Pharma

Consulting or Advisory Role: Cell Design Laboratories, Bristol-Myers Squibb, RXi Pharmaceuticals

Stephanie L. Goff

No relationship to disclose

Richard M. Sherry

No relationship to disclose

Udai S. Kammula

No relationship to disclose

James C. Yang

Research Funding: Kite Pharma (Inst)

Patents, Royalties, Other Intellectual Property: Patents held by the National Cancer Institute (Inst)

Steven A. Rosenberg

Patents, Royalties, Other Intellectual Property: The National Cancer Institute has cooperative research and development agreements with Kite Pharma and Lion Biotechnologies (Inst)