The immune system’s fight against cancer

Cancer is the second leading cause of death worldwide. Obviously, the complex cancer biology and simultaneous failure of our body to halt the transformation of a normal cell into cancer cell need to be understood. Our immune system is known for its ability to fight off infections, but also plays a vital role in preventing cancers. This is achieved in a similar way to the destruction of invading bacteria and viruses, with our immune cells recognizing the cancer as different from normal cells. These dissimilarities allow the immune cells to kill the developing tumor whilst protecting the normal tissue. Although this system is effective, cancers have developed many ways of evading anti-tumor immunity. Moreover, cancerogenesis is not a static but rather a dynamic process during which tumor cells acquire mutations and genomic instability and become immortal. The reductionist view would concentrate on just cancer cells. However, tumors are rather complex “organs” settled in a tumor microenvironment with immunosuppressive signals making attacks by immune cells and therapeutics a challenge. Overcoming tumor immune evasion is a crucial strategy which is beginning to be employed in cancer therapies today.

The failure of the immune system

The last 20 years have seen a surge in research into the ways cancer avoids destruction by the immune system. Key factors which have been identified include the production of immune-suppressing chemical signals or ‘cytokines’ by the tumor and its tumor microenvironment, the removal of key tumor-recognition proteins and the activation of brakes on the immune cells. These processes each contribute to the ability of a tumor to conceal itself from the immune system, meaning the cells appear normal and the cancer is able to grow. Most immunotherapy strategies aim to re-educate the cells of the immune system to combat the evasion, rather than traditional therapies which target the cancer directly. This bears a resemblance to the use of vaccination to protect against disease, in that it enhances natural immunity to produce a specific response against the chosen target. Some therapeutics such as monoclonal antibodies recognize antigens expressed on tumor cells to target the drug and destroy the cancer. However, some cancer cells share these antigens with normal cells leading to toxicity and on-target/off-tumor adverse effects. Additionally, tumors are champions of deception and disguise when it comes to hide away from patrolling immune cells and immunotherapies by sometimes losing their tumor antigens and switching to express neo-antigens, thus they become refractory to a given therapy.

Checkpoint inhibitors – releasing the brakes on the immune system

An important strategy used in immunotherapy involves releasing the ‘brakes’ that cancer can apply to the immune response. This process was discovered in the 1990s by Nobel Prize winners of 2018 Tasuku Honjo and Jim Allison. Honjo and Allison unearthed signals which cancers are able to send, silencing immune cells even when they recognize the tumor[1]. The breaks are termed ‘immune checkpoints’ as they are activated to prevent an excessive immune response. Once they had discovered the checkpoints, the scientists then went on to develop therapeutic monoclonal antibodies which block the brake signals PD-1 and CTLA-4 expressed on T cells or PD-L1 found on tumor cell surface, leading to enhanced tumor killing. The success of the treatments of immune checkpoint blockade (ICB) astonished oncologists, with improvements in survival in some of the most challenging cancers[2]. Nevertheless, despite first enthusiasm we have learned meanwhile that not all patients benefit from ICB, response rates differ from tumor entity to entity and there are some safety issues.

Cellular strategies

The field of cancer immunotherapy has been recently moving into cellular approaches to generate powerful T cell responses. More recently, the advent of gene-editing technologies has allowed scientists to edit the immune cells directly, rather than using antibodies to interfere with them. This facilitates more fundamental change to the action of the immune system and does not rely on specific immune checkpoints. Chimeric antigen receptor (CAR) T cells are immune cells which have been edited to recognize a protein which they would normally ignore, allowing the cells to be targeted against a specific cancer, thus facilitating personalization for individual patients. The technology is yet to be used successfully in solid cancers but has substantially improved the survival rate of various blood cancers. Countless case studies show patients living cancer-free for years following CAR-T treatment, even after the failure of many other therapies[3]. But CAR-T cells are associated with severe side effects and represent a genetically stable modification, i.e. therapies on the market cannot be “switched-off”. Other promising approaches such as tumor-infiltrating lymphocytes (TILs) are in various stages of preclinical and clinical development as based on first break-through clinical tests in patients with metastatic melanoma by Rosenberg et al.[4]

The battle is far from over

Despite the success of immune checkpoint inhibitors and T cell receptor editing, there are still major challenges to be overcome in immunotherapy. Both strategies rely on the activation of individual pathways, reducing the proportion of patients who respond to treatment. Depending on a single pathway also increases the chance of cancers developing resistance to treatment, seen frequently in anti-PD-1 therapy pioneered by Allison^[5]. Similarly, resistance is seen in many CAR-T patients due to the need for universal presentation of the target protein on all tumor cells – something not often seen in cancer[6]. These shortcomings have led to a push for new strategies to provide treatments for a greater number of patients. The early success of such novel approaches and the struggle to identify new, master checkpoints such as Cbl-b indicates that the immunotherapy revolution has only just begun.

[1] Beer, G., 2021. Nobel Prize 2018: How Allison and Honjo turned immune cells against cancer – Cancer Research UK – Cancer News. [online] Cancer Research UK – Science blog.

[2] Johns Hopkins Medicine Newsroom. 2021. Favorable Five-Year Survival Reported For Patients With Advanced Cancer Treated With The Immunotherapy Drug Nivolumab.

[3] Uchicagomedicine.org. 2021. Three years after CAR T-cell therapy for lymphoma, patient still cancer-free – UChicago Medicine.

[4] Rosenberg SA et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994 Aug 3; 86(15):1159-66

[5] Pires da Silva, I., 2021. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. The Lancet, 22(6), pp.836-847.

6 Cheng, J., 2019. Understanding the Mechanisms of Resistance to CAR T-Cell Therapy in Malignancies. Frontiers in Oncology.