New Pre-clinical Research Shows Transcription-Targeting Drug Useful in T-cell Lymphoma

Peripheral T-cell Lymphomas (PTCL) are uncommon, but aggressive forms of non-Hodgkin lymphoma that develop from mature T cells, a type of white blood cell. The most prevalent subtypes include PTCL-NOS (not otherwise specified), AITL (angioimmunoblastic T-cell lymphoma), and ALCL (anaplastic large cell lymphoma). Patients with PTCL are usually treated with a combination of chemotherapy agents, mostly commonly CHOP (cyclophosphamide, adriamycin, vincristine and prednisone). With the exception of a rare variant called ALK-positive ALCL, only about a third of all patients could enjoy long-term disease-free survival, with most patients either having diseases resistant to treatment or recurrent after chemotherapy. As PTCL evolves, it becomes even more molecularly complex due to factors in the tumor microenvironment that make it hard to treat. Ongoing research has been performed in order to try and improve treatment options and increase overall survival for patients with this challenging disease.

To ultimately cripple tumors in patients with PTCL and eradicate the disease from the body, it’s necessary to target the molecular feature of PTCL that helps it grow. Leandro Cerchietti, M.D. Jia Ruan, M.D., Ph.D., and other collaborators from the Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian are trying to do just that. New research conducted by the team has shown positive results for this hard-to-treat cancer.

Dr. Cerchietti and his research group have discovered that PTCL are sensitive to THZ1, a drug that targets transcription, the first step during gene expression when DNA is copied into RNA. THZ1 was developed by Dr. Nathanael S. Gray and collaborators from the Dana-Farber Cancer Institute. THZ1 works by stopping an enzyme called CDK7 (cyclin-dependent kinase 7) that controls the transcription of lymphoma genes. This interference changes the cells and primes the tumor to better respond to biologic agents, such as BCL2 inhibitors.

For this work, Dr. Cerchietti’s Lab established a collaboration with Drs. Nathanael S. Gray from Dana-Farber and Graciela Cremaschi from the Institute for Biomedical Research and the National Research Council of Argentina. After testing more than 120 FDA-approved compounds and new biologic agents from the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health and the Meyer Cancer Center Pre-Clinical Oncology Pharmacy, the investigators found that PTCL are susceptible to inhibitors of the proteasome, epigenetic drugs and compounds that target transcription, like THZ1.

tcell-lymphoma-graphic_cerchietti_thz1According to Cerchietti, they decided to focus on THZ1 since it demonstrated pre-clinical activity against PTCLs harboring the hard-to-target mutation STAT3. STAT can drive T-cell lymphomas and other tumors when activated by extracellular signaling that involves the phosphorylation of intermediate proteins like JAK. Although inhibitors of JAK proteins have been developed, they are thought to be inactive in tumors harboring the STAT3 mutation that does not require the activity of JAK. STAT proteins drive tumors by inducing the transcription of oncogenes like MYC and BCL2. Since this process requires CDK7, THZ1 can decrease the activity of STAT and the production of BCL2 and other proteins.

“Growing scientific evidence supports CDK7 inhibition as a treatment approach for cancers that are dependent on a high and constant level of transcription,” said Dr. Cerchietti. “Targeting CDK7 with THZ1 offers a way to circumvent the aggressive pathway responsible for tumor growth in many cancers, but particularly T-cell lymphomas which respond more positively to BCL2 inhibitors.”

BCL2 inhibitors are a class of drugs that are being tested to treat a variety of blood cancers. Venetoclax is an FDA-approved BCL2 inhibitor that is used to treat chronic lymphocytic leukemia (CLL) with a specific mutation.

“We are excited about these research results and the potential to bring a new treatment to patients with this aggressive lymphoma who otherwise have very few options if their cancer does not respond to chemotherapy,” said Dr. Ruan who leads the T-cell lymphoma clinical program at Weill Cornell Medicine and NewYork-Presbyterian.

“We aim to create transformative medicines that control the expression of disease-driving genes and believe this treatment can provide a profound and durable benefit for patients with a range of aggressive and difficult-to-treat solid tumors and blood cancers,” said Nancy Simonian, M.D., CEO of Syros, the biopharmaceutical company that is developing a next-generation version of the THZ1 compound for clinical trials. “Building on this research, we’ve used THZ1 as the starting point to create a selective CDK7 inhibitor that has better drug-like properties for use in humans.”

According to Syros, a phase I clinical trial built on this research is slated to open later this year to test the dosing and safety in people with solid tumors. The company plans to expand into hematological malignancies once the appropriate dose has been established in the initial phase I trial.

The bulk of this work was supported by the Leukemia and Lymphoma Society through a Translational Research Program awarded to Dr. Cerchietti.

Additional Weill Cornell Medicine contributors to this research include: Florencia Cayrol, Pannee Praditsuktavorn, Tharu Fernando, Rossella Marullo, Nieves Calvo-Vidal, Jude Phillip, Benet Pera, ShaoNing Yang, Kaipol Takpradit, Lidia Roman, Marcello Gaudiano, Ramona Crescenzo and Giorgio Inghirami.


Monitoring Minimal Residual Disease in Lymphoma: The Italian Experience

Paola Ghione, MD
paola-ghione
Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.

Minimal residual disease (MRD) detection refers to a group of techniques used to find a very small amount of disease, normally undetectable with imaging or clinical exam. Usually, this detection is performed after treatment and, in many cases, is predictive of outcomes such as whether patients will relapse, and how quickly this might happen. Often, the reappearance of MRD can anticipate recurrence of lymphoma before it becomes clinically evident. In other hematologic disorders, such as acute leukemia and chronic myeloid leukemia, MRD is used in standard clinical practice to monitor disease status or to evaluate response to treatment. In the setting of lymphoma, measurement of MRD is still considered experimental, but a lot of research is taking place around the world to find the best way to perform it.

Our laboratory in Torino, Italy, run by Dr. Marco Ladetto and Dr. Simone Ferrero, leads many MRD projects for lymphoma and is part of the EuroMRD Network, an institution born in Europe to standardize MRD techniques. Currently, we look for tumor-specific DNA alterations in the blood before and after treatment using a technique called Allele-Specific Oligonucleotide (ASO)-PCR. Depending on how much tumor DNA is present in the blood, we can figure out the relative amount of tumor left in the body. Unfortunately, ASO-PCR requires an expert laboratory team, and the method is expensive and time-consuming, which makes it hard to use outside of specialized settings. In addition, it seems more reliable if performed directly on bone marrow aspirate (blood from the interior of the bone) than peripheral blood (coming from a normal vein), making it less attractive to clinicians and people with lymphoma.

New techniques that can speed the procedure and reduce the cost are being evaluated. For example, the droplet digital (dd)-PCR is interesting because it is faster and uses less material (i.e., requires less blood for the test). Another interesting method is Next Generation Sequencing (NGS), which allows the detection of several different DNA mutations at once. NGS analysis of cell-free circulating DNA(cfDNA) (the DNA present in circulating blood outside the cells) could give a lot information. Studying cfDNA from the blood could give us a more accurate picture of the lymphoma that in theory could be even better than studying DNA derived from an open biopsy at one site of disease. This is also sometimes referred to as a liquid biopsy. The reason it might be better is that the circulating cfDNA could show us mutations coming from all the sites where the tumor is actively growing, not only the one site from which the open biopsy is taken.

In Italy, although MRD is not yet available in routine clinical practice for treating lymphoma, it is being tested in some innovative clinical trials to guide treatment decisions. In some studies MRD negativity at the end of treatment is the primary goal, while in others reappearance of MRD prompts a preemptive approach. As an example, if MRD reappears when the person is off therapy, we can give a short re-treatment in order to avoid clinical relapse. In one of our clinical trials, evaluation of MRD has been used to rule out the presence of lymphoma in the cells collected prior to autologous stem cell transplantation.

Measurement of MRD has a lot of potential uses, and experience from other diseases proves that it can be practice changing. The challenges provided by more than 50 different lymphoma subtypes as well as the rapid evolution of new laboratory techniques have delayed the adoption of a universal test for MRD. In the near future, however, we expect to see MRD analysis in standard clinical practice everywhere.


FDA Approves First-Ever Targeted Marginal Zone Lymphoma Treatment

On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).

MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.

Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.

The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.

The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.

Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.

At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.


Immunotherapy Targeting Immune Checkpoint Inhibitor with Durvalumab for the Treatment of Relapsed/Refractory Lymphoma or CLL

Picture2By Jia Ruan, M.D., Ph.D.

A functional immune system is vital to control the growth of many types of cancers. Tumors can grow when tumor cells evade the immune system by modulating the tumor microenvironment through expression of inhibitory molecules such as PD-1 and PD-L1. Interaction of PD-1 receptor on T-cells with its ligand PD-L1 on tumor cells leads to T-cell exhaustion, immune dysfunction, and tumor progression. Recently therapeutic targeting of inhibitory checkpoint molecules like PD-1 and PD-L1 have shown promise as effective immunotherapy across a number of tumor types including solid tumors and lymphomas. These immunotherapies work by augmenting the patient’s immune system. The first generation of these new inhibitors include anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab, which have gained FDA approval for the treatment of melanoma and non-small cell lung cancer.

Durvalumab, also known as MEDI4736, is a human immunoglobulin (Ig) G1к monoclonal antibody (mAb) that selectively binds to human PD-L1 with high affinity and blocks its ability to bind to programmed cell death-1 (PD-1) receptor on the T-cells. As a PD-L1 inhibitor, durvalumab activates the tumor-infiltrating T-cells, allowing them to destroy the tumor cells. Essentially durvalumab acts a catalyst to reactivate the body’s immune system and destroy cancerous tumor cells.

Clinical Trial Summary 

Weill Cornell Medicine has recently opened a clinical trial for patients with relapsed/refractory lymphoma or released/refractory chronic lymphocytic leukemia (CLL) previously treated with at least one systemic therapy. The purpose of this study is to test the safety and effectiveness of durvalumab, a monoclonal antibody against PD-L1, in combination with other specific anti-lymphoma therapies, including lenalidomide plus rituximab, ibrutinib, and bendamustine plus rituximab.

The study will consist of 3 parts: dose finding, dose confirmation, and dose expansion.  Four treatment arms will be investigated:

-Arm A (durvalumab plus lenalidomide and rituximab);

-Arm B (durvalumab plus ibrutinib);

-Arm C (durvalumab plus bendamustine and rituximab);

-Arm D (durvalumab monotherapy).

Study subjects will receive treatment for approximately one year and be in follow-up for anywhere from two to five years after treatment.


New Clinical Trial: A Phase 1/2 Study to Assess the Safety & Tolerability of Durvalumab as Monotherapy & in Combination Therapy in Subjects with Lymphoma or CLL

The Weill Cornell Medicine Lymphoma Program has recently opened a new clinical trial for men and women with relapsed/refractory lymphoma or relapsed/refractory chronic lymphocytic leukemia (CLL). The study sponsor is Celgene International, and the principal investigator at Weill Cornell is Jia Ruan, M.D., Ph.D. For more information about the study, please call Catherine Babaran, RN at 212-746-2651 or e-mail Catherine at cmb9017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 years and older.
  • Patients with relapsed/refractory lymphoma or relapsed/refractory CLL previously treated with at least one systemic therapy.
  • Detailed eligibility reviewed when you contact the study team.

Study Summary

This clinical trial is for men and women with relapsed/refractory lymphoma or relapsed/refractory chronic lymphocytic leukemia (CLL) previously treated with at least one systemic therapy.

The purpose of this study is to test the safety and effectiveness, as well as to define the appropriate dose and schedule of an investigational drug and investigational combinations of drugs. Durvalumab is an antibody (a protein that works with your immune system) that attaches to a molecule known as “programmed-cell-death ligand 1” (PD-L1). Signals from PD-L1 help cancers avoid detection by the immune system. Durvalumab blocks these signals, interfering with the cancer’s ability to escape the immune system.

The study will consist of 3 parts: dose findings, dose confirmation, and dose expansion. Four treatment arms will be investigated:

  • Arm A (durvalumab plus lenalidomide and ritxuimab)
  • Arm B (durvalumab plus ibrutinib)
  • Arm C (durvalumab plus bendamustine and rituximab)
  • Arm D (durvalumab monotherapy)

Study subjects will receive treatment for approximately one year and be in follow-up for anywhere from two to five years after treatment.

During each 28-day treatment cycle, subjects will receive durvalumab infusion on Day 1 of Cycles 1 through 13 at a fixed dose of 1500 mg every 4 weeks in combination with:

  • Arm A: Lenalidomide orally once daily on Days 1 to 21 of each cycle for 12 months or until disease progression plus rituximab infusion on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 of Cycles 2 through 5.
  • Arm B: Ibrutinib continuous, once daily until disease progression.
  • Arm C: Bendamustine infusion on Days 1 and 2 of Cycles 1 through 6 plus rituximab infusion on Day 2 of Cycles 1 through 6.
  • Arm D: Durvalumab monotherapy arm.

Unmasking a Killer: How Immunotherapy Helps Your Body Find Cancer and Destroy It

One of the difficulties in treating all cancers is the inability of a person’s immune system to target cancer cells because of the cancer cells ability to avoid detection. Researchers throughout the Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian have been researching new ways to help the immune system find these cancer cells. This field of research is known as immunotherapy. Immunotherapy is a type of biological therapy that helps the immune system fight cancer through the use of substances in the living organism. You can find more information and an explanation as to how immunotherapy fights cancer in the below video:

http://www.nyp.org/cancerunmasked/

While specific immunotherapy derived treatments are still in the clinical trial phase for lymphoma this is an area of active research. In this video Lymphoma Program Director, Dr. John P. Leonard refers to the development of immune checkpoint inhibitors as an, “…important new frontier…” in the treatment of lymphoma. Currently clinicals for lymphoma related immunotherapy are ongoing. Available trials for immunotherapy at Weill Cornell can be found on the Joint Clinical Trials website.


World Health Organization Says Herbicide May Cause Non-Hodgkin Lmyphoma

Glysophosate is a herbicide with the highest production volume of all herbicides. In the United States it is currently marketed under the trade name Roundup, and use has increased with the introduction of genetically modified crops resistant to glysophosate. Recently experts from the International Agency for Research on Cancer of the World Health Organization met and assessed the carcinogenicity of different herbicides. In glysophosate they found an increased risk for non-Hodgkin lymphoma:

Case-control studies of occupational exposure in the USA,14 Canada,6 and Sweden7 reported increased risks for non-Hodgkin lymphoma that persisted after adjustment for other pesticides. The AHS cohort did not show a significantly increased risk of non-Hodgkin lymphoma. In male CD-1 mice, glyphosate induced a positive trend in the incidence of a rare tumour, renal tubule carcinoma. A second study reported a positive trend for haemangiosarcoma in male mice.15 Glyphosate increased pancreatic islet-cell adenoma in male rats in two studies. A glyphosate formulation promoted skin tumours in an initiation-promotion study in mice.

Glyphosate has been detected in the blood and urine of agricultural workers, indicating absorption…Glyphosate and glyphosate formulations induced DNA and chromosomal damage in mammals, and in human and animal cells in vitro. One study reported increases in blood markers of chromosomal damage (micronuclei) in residents of several communities after spraying of glyphosate formulations.16 Bacterial mutagenesis tests were negative. Glyphosate, glyphosate formulations, and AMPA induced oxidative stress in rodents and in vitro. The Working Group classified glyphosate as “probably carcinogenic to humans”.

We will continue to follow this story as more information becomes available and update guidelines accordingly.