STANFORD MULTIDISCIPLINARY CUTANEOUS AND T-CELL LYMPHOMA PROGRAM (MCTLP)
The Stanford Multidisciplinary Cutaneous and T-cell Lymphoma team offers expert treatment for patients with cutaneous or systemic T-cell lymphomas, including mycosis fungoides (MF), Sézary syndrome (SS), CD30+ lymphoproliferative disorders (lymphomatoid papulosis and anaplastic large cell lymphoma), subcutaneous panniculitis- like T-cell lymphoma, gamma-delta T-cell lymphoma, CD8+ aggressive epidermotropic T- cell lymphoma, NK/T-cell lymphoma, other peripheral T-cell lymphomas, and cutaneous B- cell lymphomas. Our physicians subspecialize in treating these types of cancers, and have extensive expertise in handling the most complicated cases. In fact, we serve as the consultants to the experts. Consultations are comprehensive and clinic visits are coordinated to allow joint evaluations by our multidisciplinary team.
Innovative Discoveries and Treatments Available at Stanford
The Stanford team continues its leadership in bringing the cutting-edge technology platforms to the clinics testing new diagnostic and prognosticating tools and establishing biomarkers of clinical outcome. Our multidisciplinary approach allows the most comprehensive and personalized management of each patient. Moreover, we offer the newest or novel cancer treatments, such as new targeted and immunotherapies, including ones that are only available at Stanford. Examples of the new therapies available at Stanford and their clinical development updates:
- Targeted therapies that attack newly discovered tumor surface proteins, genetic and epigenetic alterations that affect cell signaling, proliferation, or survival pathways and/or the microenvironment elements, to eliminate cancer cells.
- Mogamulizumab (KW-0761) is a bioengineered, humanized monoclonal antibody against CCR4, highly expressed on tumor cells; the defucosylated technology provides enhanced efficacy. Stanford’s leadership has led to the successful completion of the phase 3 trial and the FDA approval in August, 2018.
- Brentuximab vedotin is an antibody-drug-conjugate that targets CD30, commonly expressed on tumor cells in cutaneous T-cell lymphoma (CTCL). Stanford-led clinical trial in mycosis fungoides and Sézary syndrome have shown impressive activity allowing brentuximab vedotin as a standard of care option in the NCCN guidelines. Stanford’s trial, along with the phase 3 clinical trial data, was instrumental in the recent official FDA approval in cutaneous T-cell lymphoma.
- Immune checkpoint blockade such as anti-PD-1 monoclonal antibody that unleashes the antitumor effector T cells that fight off malignant T cells in mycosis fungoides and Sézary syndrome. Promising clinical activity with durable responses were observed with pembrolizumab. Comprehensive translational studies are done to characterize the biomarkers predictive of clinical response or resistance to pembrolizumab.
Novel macrophage checkpoint blockade, anti-CD47 monoclonal antibody, specifically discovered by Stanford investigators, is undergoing clinical development in solid tumors and lymphomas including cutaneous T-cell lymphoma. Blocking the checkpoint (“don’t eat me”) with the antibody allows effective phagocytosis of the malignant cells by patient’s own macrophages. Combination therapy with mogamulizumab (anti-CCR4 antibody) may enhance the “eat-me” signal and provide improved results. Stanford will be leading a multicenter trial exploring this novel combination approach.
Anti-KIR3DL2 monoclonal antibody therapy in cutaneous T-cell lymphoma. KIR3DL2 is highly and selectively expressed on neoplastic T cell, including transformed mycosis fungoides and Sézary syndrome. This antibody works by stimulating the patient’s own immune system to attack the KIR3DL2 expressing cancer cells. In the phase 1 study, patients tolerated the humanized antibody very well and experienced significant clinical benefit, especially in those with Sézary syndrome. The early promising results has led to the development the currently ongoing phase 2 pitovtal study.
Stanford investigators have shown that low-dose (12 Gy) total skin electron beam therapy (LD-TSEBT) can be highly effective in clearing the skin disease in patients with CTCL We are exploring various combination approaches with LD-TSEBT, to not only clear lymphoma in all compartments including the blood and lymph nodes but also to provide sustaining response by partnering with immune therapies. We have successfully combined LD-TSEBT with pembrolizumab or immune cytokines such as interleukin-12. Currently, we are exploring the combination of LD-TSEBT with mogamulizumab in a clinical trial.
Clinical trial based on Stanford’s genomics research targeting the molecules and pathways that allow survival advantage of malignant T-cells is ongoing in collaboration with Memorial Sloan Kettering Cancer Center. An oral PI3K dual inhibitor, duvelisib, is combined with histone deacetylase inhibitor (romidepsin). Targeted sequencing and other correlative/translational studies are ongoing. Other trials targeting cancer cell signaling and survival pathways including a dual SYK-JAK inhibitor (cerdulatinib) and selected ITK inhibitor (CPI-818) is also ongoing inpartnerships with industry.
Non-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) using total skin electron beam therapy (TSEBT), total lymphoid irradiation (TLI), and anti-thymocyte globulin (ATG) as novel preparatory regimen for patients with mycosis fungoides and Sézary syndrome. Stanford's "protective" conditioning regimen allows patients to have long-lasting or curative results with much improved safety profile than conventional donor blood stem cell transplantation regimens. This novel Stanford regimen is now being adopted at multiple expert centers, globally. Patients referred for consideration of allogeneic transplantation will be managed jointly with our multidisciplinary group.
Chimeric antigen receptor T-cells (CAR-T) technology equips the activated T-cells with the ability to target specific molecules on the cancer cells, resulting in super potent killing of cancer cells by super-charged T-cells. With the discovery of gene editing tools, we now are able to utilize the CAR-T therapy to fight T-cell lymphoma cells specifically without the good T-cells killing each other. In partnership with CRISPR Therapeutics, CD70 targeting CAR-T therapy in cutaneous and systemic T-cell lymphomas have been initiated.
New topical agent, resiquimod, with potent immune stimulating effects target the toll-like receptors (TLRs) 7 and 8 in patients with mycosis fungoides. Resiquimod can stimulate the release of immune cytokines and enhance the anti-tumor T- cell and natural killer cell activities, thus effectively eliminate cancer cells. By turning on the systemic immune mechanism with a local application, resiquimod may show clinical activity in distant skin lesions.
Newer photodynamic therapy using topical hypericin and non-UV light source, similar to fluorescent light, is being explored as a safer, non-skin damaging option for those seeking light type of therapy. A multi-center trial is ongoing and actively enrolling. The goal of this treatment is to enable patients to use this well-tolerated light source at the comfort of their home.
Newer molecular diagnostic methods including TCR high throughput sequencing that offers superior sensitivity and specificity over conventional tools for the identification and monitoring of clonal malignant T cells. This type of technology is actively used to follow cancer activity that is not measurable by conventional methods, thus better defining and predicting if patients can be in long-term remission. The same method is also used to identify distinct malignant clones thus differentiating lymphoma from benign or inflammatory mimics, leading to early and/or more definitive diagnosis.
Sophisticated in-depth next generation sequencing (NGS) of tumor tissue and blood to identify driver/actionable new targets, bolstering our investigations towards delivering personalized/precision medicine. Stanford has led investigations to help identify key pathways and molecules used by tumor cells for their survival and spread of cancer. Stanford investigators have also developed a targeted NGS panel for hematologic malignancies that can be utilized to identify actionable (“drugable”) targets in cutaneous and T-cell lymphomas. This type of high-power sequencing technology is also being used to identify lymphoma-specific mutated or rearranged proteins that is recognized by the patient’s immune system. An example is patient-specific, rearranged tumor T-cell receptor protein. Identifying these new proteins will allow us to develop approaches that will significantly enhance the patient-specific anti-tumor immune response. Pre-clinical studies of patient- specific anti-TCR immune response have been promising and we hope to launch a clinical trial in the next couple of years.
The Stanford MCTLP team led the efforts in establishing the Cutaneous Lymphoma International Consortium (CLIC), an international collaborative network of CL expert centers for large-scale studies. The CLIC Steering Committee was established to optimize the global representation of leadership. Collectively, we recognized the potential challenges of building and sustaining an ambitious international platform, thus we identified initial objectives with stepwise build towards the ultimate goal to prepare the CLIC alliance for translational discoveries with large-scale testing and validation for optimal clinical applicability. More than 60 international expert centers have joined to partake in the CLIC collaborative effort. Stanford currently serves as CLIC’s coordinating data center for the collection and management of clinical, pathology, and molecular data linked with a federated (“virtual”) Biobank establishment at each participating center. This CLIC Biobank and digitized pathology databank will serve as an invaluable repository of clinical samples linked with prospectively collected clinical and pathology annotation for future translational research. Through this mechanism, key scientific discoveries reported from an expert center can be efficiently validated in a larger study at an international level.
CUTANEOUS AND T-CELL LYMPHOMA CLINICAL TRIALS
To learn more about active Lymphoma clinical trials, please visit: cancer.stanford.edu/trials or cutaneouslymphoma.stanford.edu
Prospective Multicenter International Observational Study for Determination of a Cutaneous Lymphoma International Prognostic Index Model and Impact of Major Therapies in Patients with Advanced Mycosis Fungoides and Sézary Syndrome
A Phase 2 Single-Center, Single-Arm, Open-Label Mogamulizumab Combined Upfront with Low-dose Total Skin Electron Beam Therapy (LD-TSEBT) in Patients with Mycosis Fungoides and Sézary Syndrome
A Phase 1b/2 Study of Hu5F9-G4 (Magrolimab) in Combination with Mogamulizumab in Relapsed/Refractory Treated T- cell Lymphoma
An Open-Label, Multi-Cohort, Multi-Center Phase II Study Evaluating the Efficacy and Safety of IPH4102 Alone or in Combination with Chemotherapy in Patients with T-cell lymphoma: TELLOMAK study
A Phase II Trial of MK-3475 (Pembrolizumab) and Interferon Gamma 1-b Combination Immunotherapy in Patients with Previously Treated Mycosis Fungoides and Sézary Syndrome
A Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Parallel-Arm Phase 2 Trial to Assess Safety, Efficacy and Pharmacokinetics of CD11301 (Resiquimod) 0.03% and 0.06% gel in the Treatment of Cutaneous T-Cell Lymphoma (CTCL), Stages IA, IB and IIA
Optimizing Dosing of Brentuximab Vedotin for Mycosis Fungoides, Sezary Syndrome, and Lymphomatoid Papulosis
A Phase 1/1b Dose-Escalation Trial Evaluating CPI-818, an Oral Interleukin-2-Inducible T-Cell Kinase Inhibitor, in Subjects With Relapsed/Refractory T-Cell Lymphoma
A Phase 1/2A Open-Label, Multi-Dose, Multi-Center Escalation and Exploratory Study of Cerdulatinib (PRT062070) in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) OR B-Cell or T-Cell Non-Hodgkin Lymphoma (NHL)
A Phase 1/2 Trial of Duvelisib (IPI-145) in Combination with Either Romidepsin or Bortezomib in Relapsed/Refractory T cell Lymphomas
Phase 3 Study to Demonstrate Safety and Efficacy of E7777 (Denileukin Diftitox) in Persistent or Recurrent Cutaneous T Cell Lymphoma
A Phase 1a/1b Dose Escalation and Expansion Trial of TTI-621, a Novel Biologic Targeting CD47, in Subjects with Relapsed or Refractory Hematologic Malignancies
A Phase 1, Open-Label, Multicenter, Dose Escalation and Cohort Expansion Study of the Safety and Efficacy or Anti-CD70 Allogeneic CRISPR-Cas9-Engineered T Cells (CTX130) in Adult Subjects with Relapsed or Refractory T or B Cell Malignancies