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Understanding Resistance Mechanism to Enhance CAR-T Immunotherapy for MCL

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy.

Analysis and Targeting of Tumor-Associated Monocytes/Macrophages that Inhibit PD-1 Blockade

Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In classic Hodgkin Lymphoma (cHL), PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy. We have identified a major population of monocyte/macrophages in patients with cHL that inhibit tumor cell killing and limit the efficacy of PD-1 blockade.

Therapy Acceleration Program - Portfolio

Since 2017, three TAP-supported therapies have been approved by the U.S.

Developing Novel CAR-T Cell Therapy For Hematologic Malignancies

We observed that patients with many hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that can kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in vivo. In this proposal, we will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities.

A phase 1 study of KT-333, a STAT3 protein degrader, in patients with NHL

In March 2020, LLS made an equity investment in Kymera Therapeutics to "Support Studies with Protein Degraders for Development in Hematological Patients."

The Immune Niche in the Development of Hematological Malignancies and Implications for Novel Therapy

Our SCOR Program, composed of four complementary Projects supported by three shared Cores, is designed to determine how the immune niche and factors in its composition and regulation affect the initiation and progression of hematopoietic malignancies. Using genetically engineered mouse models, cell cultures and patient samples, the power of multi-omics analyses will be brought to bear to identify common drivers and expose underlying mechanisms.

Family Support Groups

The Leukemia & Lymphoma Society (LLS) Family Support Groups program gives patients and their families a place to go where they can share information, education and feelings in a comfortable and caring environment. Family Support Groups are for anyone affected by blood cancer and are free. There are currently 230 groups near some of our chapters and in outlying areas, with the number of groups growing each year. Groups generally meet once a month at a library, a local conference room or at LLS's chapters.

Novel CD7 CAR T-cells for refractory T-cell malignancies affecting pediatric and AYA patients

T-cell leukemias and lymphomas have devastating outcomes if they recur after or don’t respond to standard treatment, with the only hope of cure being bone marrow transplant (BMT). Unfortunately, many pediatric, adolescent and young adult (AYA) patients are unable to achieve clinical remission (and thus unable to proceed to BMT) with standard salvage therapies, which are often even more toxic than upfront therapies.

A phase 1/2 study of BI-1206, a monoclonal antibody to CD32b (FcyRIIB), in combination with rituximab in patients with indolent NHL that has relapsed or is refractory to rituximab

In January 2023, LLS made an equity investment in BioInvent to "Support Clinical Development of BI-1206 for NHL Indications and BI-1808 for T-Cell Lymphoma Indications Including CTCL."

Targeting HSP70 to Immune Effector Cells to Overcome the Immune Suppressive Myeloma Microenvironment

Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma.

A phase 2 trial of EO2463, a novel microbial-derived peptide therapeutic vaccine, as monotherapy, and in combination with lenalidomide and rituximab, for treatment of patients with indolent NHL

In October 2023, LLS made an equity investment in Enterome to "support the ongoing Phase 2 SIDNEY study of EO2463 in indolent non-Hodgkin B-cell lymphoma."

Christina

As a Greek Latina indie author, I found it empowering to share my fight with lymphoma through social media and with my current writing. Many have told me that it’s inspiring, and I hope that leads to more attention and support for those fighting blood cancers like lymphoma.

Hollis

I was diagnosed with lymphoma in January and it has been an uncertain journey since then. I’m still unsure of what lymphoma means to me. Because I haven’t been able to answer this question, I have been reticent to share my diagnosis with others. Am I a cancer “victim?” Does cancer define me? Should I be advocating for Lymphoma care and awareness this September? I’m far from the first person to grapple with a cancer diagnosis, but this month I am compelled to finally share my Lymphoma diagnosis.

Erica

Erica was diagnosed with potentially fatal Stage 4 Hodgkin Lymphoma on March 28, 2013. Her journey to survive her battle with cancer was very trying but after overcoming her obstacles, Erica is very passionate about inspiring people to have the d’zire to survive any challenges that they may face in their lives. Erica’s fight to survive lymphoma had its highs and its lows, however, she didn’t give up even when at times her battle seemed like it wasn’t getting any easier.

Max

My son Max was diagnosed with B-cell lymphoma in May 2017, just 10 days before his 19th birthday. He discovered a lump under his chin a few months before, and in April he noticed it had grown. After we took him to get it checked out and learned the devastating news, we were in complete shock. He had no other signs of anything else being wrong.

Kenneth

On August 24, 2017, I was diagnosed with Hodgkin lymphoma (HL). It turns out, after much back-and-forth and a second cervical excision, that I actually had diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin lymphoma (NHL).  And for good measure, kidney cancer as well. Why not two primaries, right?

Financial and Legal

Balancing Work

The many responsibilities of caring for someone often leads to job conflicts. Work is a financial necessity and a major source of personal satisfaction, but for many caregivers, it is often difficult to balance the twin responsibilities of caregiving and working. Each caregiver’s working conditions are different. Talk to your supervisor and look in the employee handbook or other human resources publications to learn about your company’s policy on caregivers.

Felicita

At age 38, I was a wife and mom of three active boys. I worked as a preschool teacher. My days were spent surrounded by children, even when I was not working. In the fall of 2018, I began feeling really tired and I was suffering from chronic back pain and abdominal pain. I also was losing a great deal of weight. Then one evening while stretching, I felt a large lump on the left side of my abdomen. I panicked and made an appointment with my primary care physician.

Lorna

I was diagnosed with Stage 4 NH large B-Cell primary hepatic lymphoma in April, 2013. I was told by my doctor that this was a very rare form of lymphoma with less than 200 cases in the US. I had surgery to remove 90% of the right lobe of my liver as the tumor was very large at 16cm (initially I was diagnosed with liver cancer until they removed the tumor and the pathology revealed that it was NH lymphoma).

Lisa

I lost my big brother Vincent J. Di Cristo to two forms of cancer on February 14, 2014. He apparently had both high grade B-cell non-Hodgkin lymphoma as well as Burkitt lymphoma. I’m very confused as to how he could have had two different types of cancer because as far as I know, he was always in good health.

Lisa

I am a 26-year survivor of 4B Hodgkin's lymphoma, and a 21-year survivor of non-Hodgkin's lymphoma.

I was 41 years old when I was first diagnosed, and I had three young children back then. Treatment was tough, but my husband was by my side every step of the way and it made a big difference.

My hero is my dad. He was diagnosed with Hodgkin's lymphoma in 1961 and battled the disease until 1969. He was 38, and I was only 14. Back then, they didn't have the drug regimens they have today, but they were working on getting it right.

Joy

My mother, Joy, was diagnosed in 2015 with follicular lymphoma (FL) in her stomach. She went into remission after chemo treatment. Six months later, it came back, this time more aggressive and on the outside of her organs. They did CHOP chemo and then a bone marrow transplant. She went into remission for a second time. Eight months later, she wasn't feeling spectacular, so we took her back to the doctor. She was diagnosed with large B-cell lymphoma (DLBCL). The mass was in her uterus and had grown so fast and massive that it blasted through her bladder.

Victor

Our father Victor was diagnosed in 1998 at the age of 30 with Burkitt non-Hodgkin lymphoma (BL). He was living in Los Angeles, California, at the time and had just gotten engaged to my mother, Debra. He began not feeling well and was diagnosed with a small mass in his stomach. He was told it was non-Hodgkin lymphoma (NHL). He contacted The Leukemia & Lymphoma Society (LLS), and in coordination with MD Anderson, he went to Texas, and a protocol was set in motion to fight this disease.

Sahara

In August 2021, I was diagnosed with stage IV Hodgkin lymphoma (HL). I am now cancer-free. The Leukemia & Lymphoma Society (LLS) helped me tremendously throughout my process. I had the privilege of raising money for LLS through an Instagram campaign by sharing my story online.

Nicole

In the summer of 2016, I wasn't feeling like my usual energetic self and felt tired all the time. Initially, I attributed my tiredness to my busy life as a wife and mother with a full-time job outside the home. Some of my other symptoms were weight loss, night sweats, and a persistent feeling that something was always stuck in my throat.