Expert perspective on advancements in cancer immunotherapy, including CAR-T cells, allogeneic strategies, and the role of bispecific antibodies.

Innovations in Immunotherapy: CAR T-Cells, Allogeneic Approaches, and Bispecifics

Video synopsis is AI-generated and reviewed by OncLive editorial staff.

The field of cancer immunotherapy is witnessing significant innovations, particularly in the treatment of non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL). One major challenge is the time it takes to manufacture CAR T-cell therapies, which can range from a month to a month and a half. Patients with aggressive lymphomas may require bridging chemotherapy while awaiting CAR T-cell therapy, which can be problematic if their condition deteriorates during this time.

Another consideration is whether a patient's own T cells are the optimal choice for CAR T-cell therapy. Some researchers are exploring the use of third-party donors to supply more robust T cells that have not been exposed to chemotherapy. By selecting specific T-cell subsets and genetically engineering them, it may be possible to create more potent and less toxic CAR T cells. The use of healthy third-party donors, particularly young individuals, can potentially provide T cells for hundreds of patients. However, there is a significant challenge in using allogeneic CAR T cells from third-party donors. The recipient's immune system may recognize them as foreign, leading to rejection or graft-vs-host disease. This issue has been addressed through the revolutionary gene-editing technology CRISPR-Cas9, which allows for precise modification of cells to avoid recognition by the recipient's immune system.

Allogeneic CAR T cells, which involve CRISPR-edited cells, have shown promise in clinical trials. These edited CAR T cells have demonstrated remarkable overall and complete responses in lymphoma patients, with some of these responses being impressively durable. This approach opens new possibilities for lymphoma treatment. Additionally, bispecific antibodies are emerging as another effective treatment modality. Bispecifics bring about CAR T cell­–like killing processes by using a 2-forked construct, one end binding to the cancer cell and the other to T cells. This strategy has shown impressive results, even in patients for whom CAR T-cell therapy failed, outperforming traditional chemotherapy or immune checkpoint pathway strategies in some cases.

The timing of bispecific antibody treatment remains a question, as it's unclear whether they should be administered earlier in the treatment sequence or reserved for later lines of therapy. There is currently a lack of head-to-head trials comparing bispecifics to CAR T-cell therapy, making it difficult to determine their relative effectiveness in specific lymphoma types. Both cell therapy and bispecific antibodies have their advantages and disadvantages. CAR T-cell therapy is a 1-time treatment, while bispecifics require repeated dosing over an extended period. This underscores the transformative era of cancer therapeutics, marked by a deeper understanding of the immune system and the development of a wide array of cell-based therapies, from cells to T-cell receptor-modified constructs, natural killer cell-modified CARs, macrophage CAR cells, and more. This rich landscape of therapeutic options holds promise not only for non-Hodgkin lymphomas but also for various other blood cancers, with numerous studies currently underway to unlock their potential.

Videos

Delve into the challenges of CAR T-cell therapy access and explore the biology behind treatment responses and relapses in lymphoma patients.

Challenges in CAR T-Cell Therapy for Lymphoma

CAR T-cell therapy, a promising treatment for lymphoma patients, faces significant challenges in terms of access and treatment responses. A key issue is the eligibility gap; while approximately 25,000 patients in the United States receive a diagnosis of diffuse large B-cell lymphoma (DBCL) annually, a substantial disparity exists between the number of eligible patients and those who actually receive CAR T-cell therapy.

About 60% of patients with de novo DLBCL can be cured with conventional therapies, leaving approximately 8000 patients. However, not all of them can access CAR T-cell therapy due to various factors, including insurance coverage, racial and ethnic disparities, and socioeconomic disadvantages. These disparities highlight the need to address health care access issues, ensuring that CAR T-cell therapy is available to all eligible patients. Excluding patients with access barriers, an estimated 6500 patients should be eligible for CAR T-cell therapy. Contrary to the belief that advanced age or comorbidities might preclude eligibility, research shows otherwise. In a study of real-world data, patients with comorbidities and advanced age who wouldn't have qualified for clinical trials achieved outcomes comparable to those enrolled in trials.

However, despite the potential for broad eligibility, the majority of patients with DLBCL do not receive CAR T-cell therapy, with access rates plateauing at approximately 30%. This access issue remains a significant concern in the field. Furthermore, the biology behind treatment responses and relapses poses another challenge. One of the drivers of relapse post–CAR T-cell therapy is antigen escape, where cancer cells reduce or alter the expression of CD19, the target antigen for CAR T cells . This alteration makes it challenging for CAR T cells to recognize and eliminate these cancer cells effectively. To address this issue, some centers are exploring CAR T-cell therapy strategies that target multiple antigens simultaneously, such as CD19, CD20, and CD22. This approach increases the chances of success by ensuring that if one antigen is not expressed or is altered, the CAR T cells can recognize and attack the cancer cells.

Another complication arises from the existence of alternative pathways for T cell–mediated cancer cell killing, including the FAS ligand pathway. Loss of key receptors or ligands in this pathway can hinder the effectiveness of CAR T-cell therapy. In conclusion, CAR T-cell therapy offers great potential in lymphoma treatment, but significant challenges persist in access and addressing treatment response and relapse. Overcoming health care disparities and increasing access to CAR T-cell therapy for eligible patients is essential. Additionally, ongoing research into CAR T-cell therapy strategies that target multiple antigens and address alternative pathways of cell killing holds promise for improving treatment outcomes and reducing relapse rates in patients with lymphoma.

Explore the real-world application of CAR T-cell therapy in lymphoma treatment, from response rates to its role in first-line therapy.

Real-World Use of CAR T-Cell Therapy in Patients with Lymphoma

The landscape of lymphoma treatment has witnessed a significant transformation with the advent of CAR T-cell therapy. Early studies have reported impressive overall response rates ranging from 50% to 80%, along with complete response rates ranging from 40% to 54% for patients with diffuse large B-cell lymphoma (DLBCL). These outcomes represent a substantial improvement compared to historical data, where complete response rates were predictably approximately 7%, with a 2-year survival of 16%.

What sets CAR T-cell therapy apart is its potential for long-term remission. Over years of follow-up, as many as 40% of patients who receive CAR T-cell therapy remain long-term relapse-free survivors. While not every patient responds initially, most who achieve a complete response experience enduring remission. A key question that arises is the optimal timing for employing CAR T-cell therapy. Traditionally, patients were considered for CAR T-cell therapy in the third line after receiving salvage chemotherapy and autologous stem cell transplant. However, prospective randomized trials, including the ZUMA-7 (NCT03391466), BELINDA (NCT03570892), and TRANSFORM (NCT03575351) trials, have challenged this paradigm. Two out of these 3 trials demonstrated statistically significant improvements in event-free survival. The most recent ZUMA-7 trial even showed an overall survival advantage.

This compelling evidence has raised questions about whether CAR T-cell therapy should be employed earlier, potentially in the first line, bypassing autologous stem cell transplant. The focus has shifted to patients who predictably have a lower likelihood of complete remission with primary therapy and a higher risk of subsequent relapse. Specifically, patients with high International Prognostic Index (IPI) at diagnosis and those with double or triple-hit lymphomas are the target of these new studies. The ZUMA-12 trial (NCT03761056), focused on high IPI and double or triple-hit lymphomas, employed a strategy where patients received an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine)-like regimen. After 2 cycles, they underwent an interim PET scan, and if the scan remained positive, they proceeded to CAR T-cell therapy. The results showed impressive complete remissions and durability, paving the way for the ZUMA-23 trial (NCT05605899).

The ZUMA-23 trial is a prospective multicenter study that explores upfront CAR T-cell therapy in high-risk DLBCL. Although these trials are in their early stages, the preliminary ZUMA-12 data has fueled optimism that CAR T-cell therapy might indeed become a game changer in the frontline treatment of high-risk lymphoma. As these studies progress, they hold the potential to redefine the standard of care for patients with lymphoma, providing these patients with an earlier and more effective therapeutic option. The results of these trials will play a pivotal role in shaping the future of lymphoma treatment, offering hope to patients who need innovative solutions.

Gain insights into CAR T-cell therapy's impact on lymphoma treatment through a historical perspective and mechanism of action.

CAR T-Cell Therapy’s Impact on Lymphoma Management

CAR T-cell therapy, a groundbreaking approach in lymphoma treatment, has reshaped the landscape of cancer care. A historical perspective is vital to understanding this revolutionary therapy. In 2017, the first CAR T-cell therapy, Kymriah, was approved for treating diffuse large B-cell lymphoma (DLBCL). This approval was a significant milestone in the field, offering hope for patients with relapsed or refractory DLBCL.

Three pivotal trials—ZUMA-1 (NCT02348216), JULIET (NCT02445248), and TRANSCEND (NCT02631044)—explored CAR T-cell therapy in the context of DLBCL, particularly in patients who had reached the third line of treatment. These trials involved different CAR T-cell constructs, each with distinct stimulatory domains, adding to the wealth of knowledge about CAR T-cell therapy's potential. The core idea behind CAR T-cell therapy is to harness the patient's own T cells, the immune cells responsible for recognizing and eliminating abnormal cells, including cancer cells. T cells naturally form an immunologic synapse with target cells when they detect abnormalities or differential antigen expressions. This interaction provides signals (signal 1 and signal 2) that stimulate T-cell expansion, attack, and the release of cytokines, which call in reinforcements for an immune response.

Cancer cells have evolved strategies to evade T-cell recognition, posing a challenge to immune responses. Nevertheless, advancements in T-cell biology have illuminated the intricacies of these interactions, enabling the development of novel gene transduction methods. In CAR T-cell therapy, T cells are collected from patients through a leukapheresis process, a technique similar to blood donation, which separates white blood cells where T cells reside. In the laboratory, T cells are isolated and genetically engineered, most commonly using a non-replicating virus vector that carries a gene cassette. This gene cassette includes components for the CAR, the artificial construct that equips T cells to target specific antigens on the cancer cells. The CAR comprises a fragment of an antibody that recognizes the target antigen, a hinge region, and a transmembrane region to anchor it to the T-cell membrane. Inside the T-cell, signal 1 and signal 2 molecules stimulate T-cell activation, expansion, and cytokine release.

CAR T-cell therapy diverges from native T-cell receptor recognition, as it doesn't rely on the major histocompatibility complex (MHC) presentation of antigens. CAR T cells can directly target any antigen expressed on the cancer cell's surface, making them versatile tools for cancer treatment. Once the CAR construct is integrated into the T cell's DNA, the engineered T cells are expanded to reach a billion cells before being infused into the patient. These CAR T cells , guided by the CAR's fragment of antibody, seek out the target antigen, often CD19 in the case of diffuse large B-cell lymphoma. The therapy has proven to be a game changer, offering new possibilities for treating not only DLBCL but also other CD19-expressing lymphomas, including mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, and B-cell acute lymphoblastic leukemia.

In conclusion, CAR T-cell therapy has evolved into a transformative approach in lymphoma treatment. Its mechanism of action, rooted in T-cell biology and genetic engineering, allows for precision in targeting and eliminating cancer cells, making it a promising tool for improving outcomes and providing hope for patients with challenging lymphoma subtypes.

Discover cutting-edge cellular therapeutics, CAR T-cell therapy, and bispecific strategies for treating lymphoma patients in clinical trials.

Advancing Lymphoma Treatments: CAR T-Cell and Bispecific Therapies 

In the realm of lymphoma treatment, cutting-edge cellular therapeutics are redefining the landscape, offering new hope for patients with challenging cases. Beyond the well-known rituximab, one of the most promising approaches in lymphoma treatment is CAR (chimeric antigen receptor) T-cell therapy, which is currently being investigated in a multicenter trial. This therapy is particularly focused on patients with double and triple hit lymphomas, a subset known for its aggressive nature. A prospective randomized trial is underway to evaluate the use of cellular therapeutics in the frontline treatment of lymphoma patients. In this trial, patients with high International Prognostic Index (IPI) scores and/or double or triple-hit genetic rearrangements are initially treated with an R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]-like regimen. After 2 cycles of therapy, response assessment is conducted using PET scans. If the PET scan still shows significant disease activity, patients are transitioned to CAR T-cell therapy. This strategy, employed in an early phase 1 trial, aims to provide more effective treatment for patients who might not respond optimally to standard regimens.

CAR T-cell therapy involves a biological approach to target large cell lymphoma. It leverages the interaction between an antigen, often CD-19 on cancer cells, and an anti-CD3 antibody on T cells . This interaction brings T cells close to cancer cells, facilitating the formation of an immunologic synapse. This allows the T cells to release perforin, create pores in the cancer cells, and unleash granzymes, which trigger a cascade of nucleases that ultimately lead to the digestion of the cancer cell's DNA. Another emerging approach in lymphoma treatment is bispecific antibodies. These antibodies follow a similar strategy, bringing T cells and cancer cells into proximity to enhance T-cell activity and eliminate cancer cells more effectively. Bispecifics are of particular interest in certain patient populations, including those with high IPI scores and patients with cytogenetic abnormalities predictive of poor outcomes.

Overall, these innovative approaches represent a significant shift in the management of lymphoma. They offer new possibilities for patients with challenging lymphoma subtypes, such as double and triple hit lymphomas, who may not respond well to traditional treatments. As clinical trials continue to explore the potential of CAR T-cell therapy and bispecific antibodies, the future of lymphoma treatment holds promise for improved outcomes and a broader range of therapeutic options. In conclusion, the evolving field of cellular therapeutics, including CAR T-cell therapy and bispecific antibodies, is expanding treatment possibilities for lymphoma patients, particularly those with high-risk features or refractory disease. These therapies offer new hope for achieving more effective and precise outcomes in lymphoma management.

Advancing Lymphoma Treatments: CAR T-Cell and Bispecific Therapies

Expert insight into current treatment strategies and emerging therapies for diffuse large B-cell lymphoma, a challenging malignancy.

Large B-Cell Lymphoma: Treatment Approaches and Evolving Therapies 

Diffuse large B-cell lymphoma (DLBCL) presents unique challenges in its treatment, and the transcript delves into the evolving landscape of therapeutic approaches. The standard of care for the majority of DLBCL patients has been R-CHOP, a regimen combining rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Although this treatment has been effective for several decades, recent clinical trials are exploring new options, with the addition of a drug called polatuzumab challenging R-CHOP's status as standard-of-care.

For more aggressive, rapidly proliferating cases and double or triple-hit lymphomas, an intensified regimen called R-dose-adjusted EPOCH (R-EPOCH) with the addition of etoposide is employed. Additionally, R-EPOCH plays a significant role in treating high-grade, rapidly proliferating Burkitt lymphoma. Approximately 60% of patients with DLBCL achieve remission with frontline R-CHOP–like therapy, leaving 40% who either don't achieve complete remission (primary refractory) or relapse after initial treatment. Historically, these patients have undergone salvage chemotherapy, utilizing regimens such as R-GemOx (rituximab, gemcitabine, and oxaliplatin), R-ICE (rituximab, ifosfamide, carboplatin, etoposide), or R-DHAP, (rituximab, cisplatin, cytosine arabinoside, dexamethasone) with no definitive superiority among them. Treatment choice often depends on individual centers or practitioners.

Patients with chemotherapy-sensitive disease may become candidates for autologous stem cell transplant. However, a significant percentage of patients do not respond to salvage chemotherapy, presenting a challenging prognosis. Recent advancements in cellular therapeutics and bispecific antibodies are changing the landscape. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential game-changer for patients with relapsed or refractory DLBCL. As part of tailoring treatments to individual patients, some regimens may exclude doxorubicin due to its potential for cardiotoxicity, especially in those with preexisting heart conditions. Regimens are adapted for older patients with various comorbidities such as heart disease, diabetes, or lung disease. In the context of evolving therapies, there's a growing need for consensus among health care teams. The lymphoma care team at the University of Kansas meets to discuss individual patient cases and formulating tailored treatment plans. This is particularly crucial for advanced-age patients with significant comorbidities.

In summary, the treatment landscape for DLBCL is continuously evolving. Although R-CHOP has been the mainstay, ongoing clinical trials and emerging therapies, such as CAR T-cell therapy, offer new hope for patients who previously had limited options. The approach to treatment must be tailored to the individual patient, considering their age, overall health, and comorbidities, as the field continues to make significant strides in improving outcomes for patients with DLBCL.

Large B-Cell Lymphoma: Treatment Approaches and Evolving Therapies

Explore the diverse ways large B-cell lymphoma can manifest, the diagnostic process, and prognostic indicators for effective management.

Understanding LBCL: Presentation, Diagnosis, and Prognostic Indicators

Lymphoma, a diverse group of cancers affecting the lymphatic system, can present in various ways, making early detection and diagnosis critical. Patients may notice self-palpated adenopathy during daily activities like showering, while others experience deep intra-abdominal or intra-pelvic disease, leading to abdominal discomfort and non-specific complaints. Lymphomas can emerge in lymphoid tissues, lymph nodes, the spleen, and even the liver, presenting a wide spectrum of symptoms and locations. Unexplained intermittent fevers, night sweats, and unintended weight loss can serve as constitutional symptoms suggestive of lymphoma.

Medical evaluation becomes necessary when patients exhibit these symptoms, often revealing lymphadenopathy, enlarged spleens, and occasionally palpable abdominal or pelvic masses. Laboratory tests, including complete blood counts, are conducted to assess potential bone marrow involvement. In some cases, lymphomas manifest with cytopenias or abnormal circulating cells, while a rare subset enters a leukemic phase. Further evaluation includes imaging studies such as CT scans and PET scans, which aid in determining the extent and aggressiveness of the disease. Additionally, laboratory studies, like LDH, help gauge cell turnover and disease propagation. The International Prognostic Index, based on age, LDH, nodal sites, and extra nodal disease, provides valuable prognostic insights.

For precise diagnosis, excisional biopsies of lymph nodes, bone marrow, or bone lesions are performed. The specific subtype of non-Hodgkin's lymphoma is identified, with common types including marginal zone, follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). DLBCL, a B-cell lymphoma, represents the most prevalent non-Hodgkin lymphoma in adult US patients. Molecular studies, like c-MYC translocation and BCL2/BCL6 genetic rearrangements, provide further prognostic information. Lymphoma patients undergo staging through bone marrow biopsies, CT scans, and PET scans. Some lymphomas can manifest in sanctuary sites like the testes and the central nervous system, causing specific clinical manifestations that require investigation. Lymphoma patients can be categorized into subgroups, such as germinal center B-cell lymphoma (GCB) and activated B-cell phenotype, which carry prognostic significance. Recent research focuses on understanding the diverse genetic profiles and their response to various therapeutic agents in these entities.

In conclusion, lymphoma's clinical presentations are broad, and diagnosing the specific subtype is crucial for planning treatment. Prognostic indicators like genetic rearrangements and the International Prognostic Index provide valuable insights into the course of the disease. Tailoring treatment strategies to these factors is essential for improved outcomes in patients with lymphoma.

Joseph P. McGuirk, DO

Articles

Innovations in Immunotherapy: CAR T-Cells, Allogeneic Approaches, and Bispecifics

Challenges in CAR T-Cell Therapy for Lymphoma

Real-World Use of CAR T-Cell Therapy in Patients with Lymphoma

CAR T-Cell Therapy’s Impact on Lymphoma Management

Advancing Lymphoma Treatments: CAR T-Cell and Bispecific Therapies

Large B-Cell Lymphoma: Treatment Approaches and Evolving Therapies

Understanding LBCL: Presentation, Diagnosis, and Prognostic Indicators