Immunological Disorders and Immunotherapy
Open Access

Challenges in Checkpoint Inhibitor Therapy and its Treatment

Willam Joes^{* *}Correspondence: Willam Joes, Department of Immunology, University of Cambridge, Cambridge, United Kingdom, Email:

Author info »

Description

Checkpoint inhibitors have revolutionized cancer therapy by controlling the body's immune system to fight tumors. These immunotherapeutic agents target specific proteins, known as immune checkpoints, which normally act as brakes on the immune response. By blocking these checkpoints, checkpoint inhibitors activate the immune system, enabling it to recognize and destroy cancer cells more effectively. Despite their success in treating various cancers, including melanoma, lung cancer, and renal cell carcinoma, checkpoint inhibitor therapy is not without challenges. This article discusses about the key obstacles in checkpoint inhibitor therapy, the mechanisms behind these challenges and the strategies being developed to overcome them [1].

Role of checkpoint inhibitors

The immune system uses a complex network of signals to distinguish between normal cells and pathogens or abnormal cells, such as cancer cells. Under normal conditions, immune checkpoints help maintain immune homeostasis by preventing excessive immune activation that could lead to autoimmunity or tissue damage [2]. However, cancer cells can exploit these checkpoints to evade immune detection and destruction. The most well-known immune checkpoints targeted in cancer therapy are Programmed cell Death Protein-1 (PD-1), Programmed Death-Ligand 1 (PD-L1) and Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4). Checkpoint inhibitors such as nivolumab and pembrolizumab (targeting PD-1), atezolizumab (targeting PD-L1) and ipilimumab (targeting CTLA-4) have shown impressive results in clinical trials, leading to durable responses and prolonged survival in some patients [3]. However, these successes are tempered by significant challenges that limit their effectiveness and accessibility. Checkpoint inhibitors are a class of immunotherapy drugs that have revolutionized cancer treatment by harnessing the body's immune system to attack and eliminate cancer cells [4]. These drugs target key proteins, known as immune checkpoints, which cancer cells exploit to evade detection and destruction by the immune system. By blocking these checkpoints, checkpoint inhibitors restore the ability of immune cells, particularly T-cells, to recognize and attack tumors [5].

Checkpoint inhibitors in cancer therapy

The immune system's primary role is to detect and destroy foreign invaders, such as viruses, bacteria, and abnormal cells like cancer. T-cells, a type of white blood cell, play an important role in this process by identifying and killing infected or cancerous cells [6]. However, to prevent excessive immune responses that could harm normal tissues (autoimmunity), the immune system employs various regulatory mechanisms, including immune checkpoints. Immune checkpoints are proteins found on the surface of T-cells or their target cells [7]. They act as signals or brakes that regulate the activation of T-cells. Under normal circumstances, these checkpoints maintain immune homeostasis and prevent autoimmunity. However, tumors can exploit these checkpoints to protect themselves from immune attack, allowing cancer to progress unchecked. Checkpoint inhibitors work by blocking these inhibitory signals, effectively releasing the brakes on the immune system and allowing T-cells to resume their attack on cancer cells [8].

Challenges of checkpoint inhibitors

Despite the success of checkpoint inhibitors in treating certain cancers, there are several challenges associated.

Tumor heterogeneity: Tumors are often heterogeneous, with different regions of the tumor expressing different levels of immune checkpoints [9].

Immunosuppressive tumor microenvironment: Tumors can create an immunosuppressive microenvironment that blunts the effectiveness of checkpoint inhibitors.

Immune-related Adverse Events (irAEs): Because checkpoint inhibitors enhance immune activation, they can sometimes cause the immune system to attack healthy tissues, leading to irAEs. Checkpoint inhibitors have transformed the environment of cancer therapy, offering renewed hope for patients with difficult-to-treat tumors [10]. However, the challenges associated with limited response rates, immune-related adverse events, high costs and the need for predictive biomarkers highlight the complexities of this treatment approach. Overcoming these challenges will require continued research and innovation, including the development of combination therapies, better management of side effects, cost reduction strategies and the identification of more reliable biomarkers. As the field of immunotherapy continues to evolve, checkpoint inhibitors will likely remain a fundamental of cancer treatment. With ongoing advancements, these therapies have the potential to become more effective, accessible and customized to the individual needs of patients, ultimately improving outcomes and survival rates in cancer care.

References

1. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: Prospective cohort study. BMJ. 2020;369.

   [Crossref] [Google Scholar] [PubMed]

2. Alvarez-Garcia J, Lee S, Gupta A, Cagliostro M, Joshi AA, Rivas-Lasarte M, et al. Prognostic impact of prior heart failure in patients hospitalized with COVID-19. J Am Coll Cardiol. 2020;76(20):2334-2348.

   [Crossref] [Google Scholar] [PubMed]

3. Hayek SS, Brenner SK, Azam TU, Shadid HR, Anderson E, Berlin H, et al. In-hospital cardiac arrest in critically ill patients with COVID-19: Multicenter cohort study. BMJ. 2020;371:m3513.

   [Crossref] [Google Scholar] [PubMed]

4. Aldabagh M, Wagle S, Cesa M, Yu A, Farooq M, Goldberg Y. Survival of in-hospital cardiac arrest in COVID-19 infected patients. Healthcare 2021; 9(10):1315.

   [Crossref] [Google Scholar] [PubMed]

5. Mandapati R, Asano Y, Baxter WT, Gray R, Davidenko J, Jalife J. Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart. Circulation. 1998;98(16):1688-1696.

   [Crossref] [Google Scholar] [PubMed]

6. Goldhaber JI, Hamilton MA. Role of inotropic agents in the treatment of heart failure. Circulation. 2010;121(14):1655-1660.

   [Crossref] [Google Scholar] [PubMed]

7. Meaney PA, Nadkarni VM, Kern KB, Indik JH, Halperin HR, Berg RA. Rhythms and outcomes of adult in-hospital cardiac arrest. Critical care medicine. 2010;38(1):101-108.

   [Crossref] [Google Scholar] [PubMed]

8. Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management. Thromb Res. 2020; 194:101-115.

   [Crossref] [Google Scholar] [PubMed]

9. Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, et al. A pathological report of three COVID-19 cases by minimal invasive autopsies. Chin J Pathol. 2020;49(5):411-417.

   [Google Scholar] [PubMed]

10. Yoshihara H, Yoneoka D. Understanding the statistics and limitations of large database analyses. Spine. 2014;39(16):1311-1312.

    [Crossref] [Google Scholar] [PubMed]