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Immune Oncology

May 30, 2024, 12:55

History of Immunotherapy: Cancer Treatment

Immunotherapy

Immunotherapy is a revolutionary approach to cancer treatment that harnesses the power of the body’s own immune system to combat malignant cells. It involves stimulating or enhancing the immune system’s ability to recognize and destroy cancer cells while leaving healthy cells unharmed. Immunotherapy works by modulating various components of the immune response, such as antibodies, cytokines, and immune cells like T-cells and natural killer cells, to target and eliminate cancer cells more effectively. This approach represents a paradigm shift from traditional cancer therapies, offering a more targeted and personalized treatment strategy with the potential for long-lasting remissions and improved patient outcomes.

Milestones in the History of Cancer Immunotherapy.

Key moments in the development of cancer immunotherapy. The image is taken from PubMed.

Immunotherapy Development

The development of cancer immunotherapy has been a long and arduous journey, spanning over a century of scientific exploration and breakthroughs. The origins can be traced back to the late 19th century when Dr. William Coley, a surgeon, observed that some cancer patients experienced tumor regression after developing bacterial infections. This led to the development of “Coley’s Toxins,” a mixture of inactivated bacteria, which was one of the earliest forms of immunotherapy.

However, it wasn’t until the late 20th century that significant advancements in understanding the immune system and cancer biology paved the way for the development of modern immunotherapies. Pivotal discoveries such as the identification of interleukin-2 (IL-2) and the production of monoclonal antibodies fostered novel techniques for studying and manipulating the immune system.

The 1980s and 1990s witnessed the approval of several groundbreaking immunotherapies by the United States Food and Drug Administration (FDA), including the tuberculosis vaccine Bacillus Calmette-Guérin (BCG), IL-2, and the CD20-targeting monoclonal antibody rituximab. These early successes laid the foundation for further exploration and development of immunotherapeutic strategies.

A major milestone was the approval of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010 for the treatment of metastatic castration-resistant prostate cancer. This paved the way for the development of other cancer vaccines, which aim to stimulate the immune system to recognize and attack tumor-specific antigens.

Immune checkpoint inhibitors and adoptive cell therapies represent two breakthrough modalities that have revolutionized cancer treatment in the past decade. Immune checkpoint inhibitors have emerged as a game-changing class of immunotherapy drugs that unleash the body’s own immune defenses against cancer cells. These agents target inhibitory checkpoint proteins like CTLA-4, PD-1, and PD-L1 that act as “brakes” on the immune system, preventing it from effectively recognizing and attacking tumor cells.

James P. Allison and Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine for their pioneering research on CTLA-4 and PD-1, respectively, which paved the way for the development of immune checkpoint inhibitors like ipilimumab (anti-CTLA-4), pembrolizumab, and nivolumab (anti-PD-1/PD-L1) for cancer treatment. Their groundbreaking discoveries unlocked a new approach to cancer therapy by harnessing the body’s immune system to attack tumor cells.

Allison’s work on CTLA-4, a protein receptor on T cells that acts as a brake on the immune system, led to the development of ipilimumab, the first FDA-approved immune checkpoint inhibitor. Ipilimumab blocks CTLA-4, releasing the brakes and allowing T cells to mount a stronger anti-tumor response. Honjo discovered PD-1, another immune checkpoint protein that suppresses T cell activity when bound to its ligands PD-L1 and PD-L2. This laid the foundation for developing pembrolizumab and nivolumab, which block the PD-1/PD-L1 pathway and reactivate exhausted T cells to fight cancer.

On another front, adoptive cell therapies, particularly chimeric antigen receptor (CAR) T-cell therapy, represent a personalized approach to cancer treatment. CAR T-cell therapy involves genetically engineering a patient’s own T-cells to express synthetic receptors that can recognize and bind to specific antigens on cancer cells, leading to their destruction. This modality has effectively treated certain hematological malignancies, such as acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. The FDA-approved CAR T-cell therapies tisagenlecleucel and axicabtagene ciloleucel have demonstrated durable remissions in some patients.

However, the success of CAR T-cell therapy in solid tumors has been limited due to various factors, including low antigenicity of tumor cells, low infiltration of effector T-cells, and diverse mechanisms of immunosuppression in the tumor microenvironment (TME). Researchers are exploring new adoptive cells therapies, such as TCR-T cells, CAR-natural killer (NK) cells, and CAR-macrophages (CAR-M) to address these challenges. These approaches have certain advantages over CAR-T cells in treating solid tumors, including better tumor infiltration, resistance to TME suppression, and the ability to target multiple antigens simultaneously.

The development of cancer immunotherapy has been a testament to the power of scientific collaboration and interdisciplinary research, drawing upon advances in molecular biology, immunology, genomics, and bioinformatics
As our understanding of the intricate interplay between the immune system and cancer continues to deepen, the future of immunotherapy holds great promise for revolutionizing cancer treatment and improving patient outcomes.

Immunotherapy Drugs

Immunotherapy drugs represent a revolutionary class of cancer treatments that harness the body’s immune system to combat malignant cells. These drugs employ diverse strategies to modulate various immune response components, either by stimulating or enhancing immune cells and molecules that can recognize and destroy cancer cells or by blocking mechanisms that cancer cells exploit to evade immune surveillance.

Early Immunotherapy Drugs

Cytokines (e.g., Interleukin-2, Interferon-alpha): Cytokines are proteins that stimulate the proliferation and activation of immune cells like T-cells and natural killer (NK) cells.

- Interleukin-2 (IL-2): This was approved in the 1990s for treating metastatic melanoma and renal cell carcinoma, achieving overall response rates of around 15-20%. While IL-2 has shown efficacy in certain cancers, its use has been limited by its short half-life, dose-limiting toxicities, and the need for high doses to achieve therapeutic effects. Ongoing research is focused on engineering IL-2 variants or formulations (e.g., IL-2 muteins, PEGylated IL-2, IL-2 immune complexes, IL-2-CD25 fusion proteins) to improve its selectivity, potency, and safety profile for cancer immunotherapy
- Interferon-alpha: While IFN-α showed modest efficacy as an adjuvant therapy after surgery for high-risk melanoma patients, the survival benefit was small. Grade 3 and 4 toxicities were common with IFN-α treatment. Ongoing research has focused on optimizing IFN-α regimens and formulations to improve its efficacy and tolerability. Studies have evaluated intermediate and low-dose regimens of pegylated IFN-α-2b, which showed some efficacy in prolonging relapse-free survival in melanoma patients. However, attempts to identify predictive biomarkers to select patients most likely to benefit from adjuvant IFN-α have been unsuccessful so far.

Cancer vaccines (e.g., Sipuleucel-T for prostate cancer): Cancer vaccines are designed to stimulate an immune response against tumor-associated antigens (TAAs) or tumor-specific mutations.

- Sipuleucel-T, approved in 2010, is an autologous cellular vaccine for metastatic castration-resistant prostate cancer. It demonstrated a statistically significant but modest improvement in overall survival compared to placebo. Sipuleucel-T did not show significant effects on time to disease progression, tumor response rates, or declines in PSA levels, as it does not directly target the tumor but aims to stimulate an antigen-specific immune response. The most common adverse events were generally mild to moderate, including chills, fever, fatigue, and headache related to the infusion of activated immune cells.

Monoclonal antibodies (e.g., Rituximab for non-Hodgkin’s lymphoma): Monoclonal antibodies target specific proteins on cancer cells or immune cells, either marking cancer cells for destruction or modulating immune responses.

- Rituximab, an anti-CD20 antibody, achieved high response rates (around 50%) when combined with chemotherapy in certain types of non-Hodgkin’s lymphoma. Direct effects of Rituximab include complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Indirect effects involve inducing apoptosis, structural changes to cancer cells, and sensitizing them to chemotherapy. The key mechanisms are CMC, where rituximab binding activates the complement system to form membrane attack complexes on target cells, and ADCC, where it binds to Fc receptors on immune effector cells like NK cells to mediate the killing of antibody-coated tumor cells.

Modern Immunotherapy Drugs

Immune checkpoint inhibitors (e.g., Pembrolizumab, Nivolumab): These drugs block inhibitory checkpoint proteins like PD-1, PD-L1, and CTLA-4, unleashing the immune system’s anti-tumor response.

- Pembrolizumab and Nivolumab (anti-PD-1) showed remarkable efficacy in melanoma, lung cancer, and other solid tumors, with durable responses in 15-20% of patients. Pembrolizumab, recommended by ASCO for stage IIB-C melanoma in a recent guideline update, emerged as an adjuvant treatment option.
- Ipilimumab (anti-CTLA-4) was the first checkpoint inhibitor approved for melanoma treatment. Higher incidence of immune-related adverse events correlated with better treatment outcomes.

CAR T-cell therapy (e.g., Tisagenlecleucel): CAR T-cell therapy involves genetically engineering a patient’s own T-cells to express synthetic receptors that can recognize and bind to specific antigens on cancer cells, leading to their destruction.

- Tisagenlecleucel and axicabtagene ciloleucel (Yescarta) are approved for certain hematological malignancies like acute lymphoblastic leukemia and non-Hodgkin’s lymphoma, respectively. In a pivotal clinical trial, 83% of patients achieved complete remission or complete remission with incomplete blood count recovery after receiving tisagenlecleucel.

Bispecific antibodies (e.g., Blinatumomab for acute lymphoblastic leukemia): Bispecific antibodies simultaneously bind to both cancer cells and immune cells, facilitating their interaction and subsequent immune attack.

- Blinatumomab, targeting CD19 on cancer cells and CD3 on T-cells, demonstrated high response rates and improved survival when combined with chemotherapy in acute lymphoblastic leukemia.

While early immunotherapies had limited success, modern treatments like checkpoint inhibitors and CAR T-cells have revolutionized cancer care, dramatically improving outcomes across a range of cancers. These advanced drugs deliver significantly more effective and durable responses than their predecessors, marking a major leap forward in oncology. They not only excel in treating blood cancers but also show enhanced targeting capabilities against solid tumors.

However, this impressive efficacy comes with a higher risk of toxicity and immune-related side effects, requiring careful monitoring and management. The use of sophisticated, personalized approaches, such as engineered T-cells, underscores the advancements in precision medicine. These cutting-edge therapies are tailored to individual patients, offering a more targeted and effective treatment strategy. As research continues, the potential for these innovative drugs to transform cancer therapy grows even greater, promising a brighter future for patients worldwide.

Future trends in immunotherapy for cancer

Personalized Cancer Vaccines: There is a growing focus on developing personalized cancer vaccines tailored to an individual’s specific tumor antigens and mutations. These vaccines aim to stimulate a more potent and targeted immune response against the patient’s cancer cells. Approaches include identifying tumor-specific neoantigens through genomic sequencing and incorporating them into vaccine formulations.
Oncolytic Virus Therapy: Oncolytic viruses are genetically modified viruses that can selectively infect and kill cancer cells while also stimulating an anti-tumor immune response. This emerging modality leverages the ability of viruses to preferentially replicate in and lyse cancer cells, releasing tumor-associated antigens and promoting antigen presentation and T-cell activation.
Combination Immunotherapies: A major focus is combining different immunotherapy modalities, such as checkpoint inhibitors with cancer vaccines, CAR T-cell therapy, or other targeted therapies. These combination approaches aim to enhance anti-tumor immunity, overcome resistance mechanisms, and achieve synergistic effects by targeting multiple pathways simultaneously.
Predictive Biomarkers: Identifying predictive biomarkers that can determine which patients are most likely to respond to specific immunotherapies is a crucial area of research. This would enable more personalized treatment strategies, improved patient selection, and better allocation of resources.
Overcoming Resistance Mechanisms: Developing strategies to overcome resistance to immunotherapies is a significant challenge. Approaches include targeting alternative immune checkpoint pathways, modulating the immunosuppressive tumor microenvironment, and investigating mechanisms of adaptive resistance to existing therapies.
Novel Targets and Approaches: Researchers are continuously exploring new targets and mechanisms within the immune system and cancer biology, leading to the development of novel immunotherapeutic approaches. These include bispecific antibodies, engineered T-cell receptors, nanoparticle-based delivery systems, and leveraging emerging concepts like ferroptosis and peroxynitrite-mediated antigen alterations.

As our understanding of the complex interactions between the immune system and cancer deepens, the future of immunotherapy holds great promise for revolutionizing cancer treatment and improving patient outcomes across a broader range of malignancies.