The immuno-oncology (IO) field represents a groundbreaking approach to cancer treatment, harnessing the body's own immune system to identify and eradicate cancer cells. This novel strategy has signaled a major advancement in the management of various malignancies, particularly those resistant to conventional therapies. The efficacy of IO has been underscored by its success in treating complex cancers, such as lung cancer, and has sparked a growing interest in therapies including immune checkpoint inhibitors (ICIs), CAR-T therapy, and antibody-drug conjugates (ADCs).

The success of these therapies has spurred significant financial investment. This investment is driven by the high therapeutic and commercial potential of IO agents, which selectively target cancer cells and enhance the immune response. Despite these advancements, challenges remain, including limited efficacy in certain patient subsets and high treatment costs, which pose affordability issues.

This article will provide a comprehensive overview of the current state of the IO market, highlighting key trends, emerging therapies, and the broader implications for the future of cancer treatment.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) function by modulating the immune system, counteracting the mechanisms that allow cancer cells to evade immune surveillance. Over the past decade, ICIs have significantly advanced cancer treatment, evolving from being secondary or tertiary options to becoming first-line therapies. Since the approval of ipilimumab for melanoma over a decade ago, the U.S. Food and Drug Administration (FDA) has approved 11 different ICIs targeting key immune checkpoints, including CTLA-4, PD-1, PD-L1, and LAG-3.

ICIs have transformed cancer treatment by moving beyond palliative care to significantly extend survival for patients with a range of cancers, including non-small-cell lung cancer, melanoma, mismatch repair–deficient colorectal cancer, bladder cancer, and Hodgkin’s lymphoma. Recent advancements support their use in adjuvant therapy for resected lung cancer and melanoma, and in neoadjuvant therapy prior to surgery. Notably, in patients with mismatch repair–deficient rectal cancer, ICIs have achieved remarkable pathological complete remissions, potentially eliminating the need for surgery.

The substantial investment in ICIs by the pharmaceutical industry is evident, with over 5,600 ongoing studies worldwide as of December 2021. These trials, involving tens to hundreds of patients each, seek to identify new uses and niches for these therapies. The financial return on ICIs is significant, with total revenues reaching approximately $60 billion in 2021. Pembrolizumab, a leading ICI, alone generated around $20 billion in sales, while other ICIs contributed single-digit billions. The lucrative nature of these drugs is attributed to their long-term administration requirements for metastatic cancer, often extending from 1 to 2 years or even indefinitely, highlighting their substantial earning potential for pharmaceutical companies.

Research is actively exploring new targets and intervention strategies to enhance therapeutic outcomes. Current preclinical and clinical studies have identified several promising co-inhibitory receptors for further investigation. These include LAG-3, TIGIT (T cell immunoglobulin and ITIM domain), TIM-3 (T cell immunoglobulin and mucin-domain containing-3), IDO (indoleamine 2,3-dioxygenase), CD39, NKG2A, and SIRPα (signal regulatory protein alpha).

In addition to co-inhibitory receptors, researchers are also examining co-stimulatory receptors that may enhance immune responses. Notable among these are ICOS (inducible T cell costimulator), GITR (glucocorticoid-induced TNF receptor family-related protein), OX40 (TNF receptor superfamily member 4), 4-1BB (TNF receptor superfamily member 9), and TLRs (Toll-like receptors). These targets represent diverse pathways that could potentially improve the effectiveness of cancer immunotherapy.

Challenges and Future Directions

Although ICIs have shown remarkable results and generated substantial revenue, they do not represent a complete solution for cancer patients. Key challenges remain:

·        Incomplete Responses: Most patients with metastatic disease do not achieve complete responses, though long-term remissions are possible in some cases, such as melanoma, non-small-cell lung cancer, Hodgkin's lymphoma, and mismatch repair–deficient tumors.

·        Limited Efficacy in Hematologic Cancers: While ICIs have proven effective for various solid tumors, their impact on hematologic cancers, other than Hodgkin's lymphoma, has been limited.

·        Toxicity: ICIs can cause significant adverse effects, including autoimmunity and severe reactions in the lungs, liver, and skin, with a 1% fatality rate.

A major hurdle is the lack of specific biomarkers to predict which patients will respond to ICIs and which will not. In the era of precision medicine, refining the approach to stimulate a targeted T-cell response against cancer-specific antigens—while minimizing global toxicity—is crucial. There is a need for accurate, clinically applicable methods to identify tumor-specific antigens and epitopes that trigger a focused cytotoxic T-cell response.

To enhance the effectiveness of ICIs, several strategies are being explored:

·        Combination Therapies: Combining ICIs with inhibitors of other repressive T-cell pathways, such as CTLA-4 and PD-1, to address additional inhibitory mechanisms.

·        Targeting Other Pathways: Investigating new targets, including TANK binding kinase 1 and various costimulatory pathways.

·        Selective Delivery: Developing methods to deliver ICIs and toxic cytokines more precisely to the tumor microenvironment, such as through tumor-specific protease-activated masking domains or intratumoral cytokine release.

·        Innovative Vaccines: Leveraging mRNA technology, similar to that used for COVID-19 vaccines, to develop new vaccine approaches.

·        Radiation Therapy: Combining ICIs with radiation therapy to potentially improve outcomes.

The current landscape of clinical trials for ICIs reveals a significant amount of redundancy, with many studies employing similar designs and statistical assumptions. Additionally, the high cost of these therapies poses a financial burden on patients and exacerbates disparities between those with and without insurance, as well as those with varying levels of healthcare access. Despite the proliferation of similar products from different pharmaceutical companies, competitive pricing has not materialized.

About  the Author    

Neeta  Ratanghayra    

Neeta Ratanghayra is a freelance medical writer, who creates quality medical content for Pharma and healthcare industries. A Master’s degree in Pharmacy and a strong passion for writing made her venture into the world of medical writing. She believes that effective content forms the media through which innovations and developments in pharma/healthcare can be communicated to the world.