Recent developments on checkpoint inhibitors,CAR T cells,and beyond for T cell-based immunotherapeutic strategies against cancer

Abstract

Objective

There was a dire need to construct a review of the recent developments on Immune checkpoint inhibitors (ICIs), CAR T Cells, and other approaches for T cell-based immunotherapeutic strategies against cancer as cancer has become one of the most fatal diseases that is responsible for causing several deaths per annum.

Data sources

Multiple published data was acquired from the high-impact factor journal articles.

Data summary

Multiple clinical strategies have been in use today such as radiotherapy, chemotherapy and immunotherapy to treat cancer of different types. Among novel cancer management strategies, the role of cancer immunotherapy by T cells has become immensely important. Cancer immunotherapy has revolutionized treatment approaches and it basically utilizes the body's immune system to treat cancer. At the forefront of this revolution, T cells are considered as the fundamental components of immune system.

Conclusions

The current review explores the therapeutic potential of T cells in the fight against cancer by applying strategies such as various ICIs (PD-1/PD-L1, CTLA-4, TIGIT, BTLA, TIM3, LAG3) and adoptive cell therapy. ICIs stimulate the body's existing anti-tumor T-cell response by the way of removing immune system inhibitors. On the other hand, in adoptive cell therapy (ACT) patient's T cells are modified to identify and attack tumor cells. Furthermore, this review also highlights significant successes that are observed with these therapies, notably PD-1 blockade and CAR T-cell therapy for various tumors. Moreover, this review also explores the potential of therapeutic vaccination, bispecific antibodies and cytokine therapy to enhance the antitumor activity. Therapeutic vaccines expose immune system to various tumor-associated antigens and training it to identify and then attack cancer cells, showing promising results in different types of cancers such as prostate cancer and melanoma. While, cytokine therapy is accompanied by the use of cytokines such as interleukin-2 (IL-2) to stimulate immune cell activity and proliferation, thereby boosting the overall anti-tumor immune response. Lastly, the current review explores the promising future of T cell-based immunotherapy, envisioning advancements in CAR design and gene editing techniques that can enhance efficacy across a broader spectrum of cancers.

Keywords

T cells cancer immune checkpoint inhibitors (ICIs)adoptive T cell therapy CAR T cells

Introduction

Cancer is characterized by an abnormal state where cells undergo uncontrolled proliferation and then cause aggressive malignancies by affecting various body regions and is synonymous with terms like malignant tumors and neoplasms.^1,2 It is also defined by its aberrant cell growth due to disruptions that occur in essential cellular processes, like cell cycle, apoptosis, DNA repair, and is influenced by the tumor microenvironment (TME), containing various types of immune cells.³ It is caused when intricate genetic changes occur within specific genes, which can either deactivate tumor suppressor genes, activate oncogenes, or disrupt stability genes that control cell growth and division.⁴ Globalization has brought about significant changes, introducing new risk factors for cancer such as addictive substances, contemporary dietary patterns, pharmaceuticals, and harmful waste materials.⁵ For instance, a study highlights that as globalization progresses, there is a convergence of risk factors such as increased alcohol and tobacco use, sedentary lifestyles and unhealthy diets across different regions, leading to increasing cancer incidences worldwide.⁶

The said ailment stands as a lethal and formidable ailment in contemporary times, leading to numerous fatalities per annum. Among all causes of death, it is considered as the second most common disease in 112 of the 183 countries studied, and third most common in the remaining 23 countries.⁷ In 2020, GLOBOCAN reported an estimated 19.3 million cancer diagnoses, resulting in approximately 10.0 million deaths attributed to cancer. GLOBOCAN projects a surge in cancer cases to 28.4 million by 2040. Female breast cancer now has the highest incidence rate at 11.7%, surpassing lung cancer at 11.4%. However, lung cancer remains the leading cause accounting for 18% of deaths, followed by colorectal cancer at 9.4%. In men, common cancers include prostate, lung and colorectal cancers while among women breast, lung and colorectal cancers are prevalent.^8,9 Overall, top ten cancers comprise 60% of new cases and account for roughly 70% of cancer-related deaths.¹⁰ The global distribution of this condition varies among different regions and is affected greatly by factors including various socioeconomic conditions and healthcare accessibility, all of which present hindrances to its efficient treatment.^11,12

This malignancy is incredibly complex and wide-ranging in its diversity, encompassing various aspects such as cellular and tissue biology, genetics, pathological characteristics, and how it reacts to different treatment approaches.¹³ Today, the major cancer treatment methods include chemotherapy,^14,15 surgery,^16,17 immunotherapy^18,19 and radiation therapy.^20,21 The cancer treatment has progressed from traditional techniques such as surgery, radiation therapy and chemotherapy to incorporate advanced strategies such as stem cell therapy, nanoparticles and targeted therapy as well as novel methods like sonodynamic therapy, chemodynamic therapy and therapies based on ferroptosis.²²

Despite the adverse effects it can induce, radiation therapy remains an essential component of cancer treatment for a substantial portion of patients, approximately 50%, of all cancer patients.^20,23 Chemotherapy, which employs cytotoxic drugs, also results in harming the healthy tissue that surrounds the tumor over time. Chemotherapy drugs are designed to affect cells that have a high natural rate of growth and renewal. This encompasses not only cancer cells but also healthy rapidly dividing cells in skin, hair, bone marrow and the lining of digestive system. This leads to notable degree of adverse effects linked with these therapies.²⁴

In addition, conventional cancer treatments often result in a variety of long-lasting side effects such as nerve damage, heart damage, kidney problems, reduced fertility, and chronic liver damage.^25–27 Cancer immunotherapy has led to substantial enhancements in both survival rates and quality of life for patients when compared to conventional treatment methods such as chemotherapy, radiotherapy, and surgery.²⁸

Cancer Immunotherapy exhibits a revolutionary shift to combat cancer. Cancer immunotherapy enhances the body's immune system to target and eliminate tumor cells while reducing unintended side effects.^29–31 It is an innovative strategy that is designed to leverage the body's own immune system to target and then finally eliminate cancerous cells.³² Immunotherapy is recommended for treating various types of cancers including breast cancer, bladder tumors, liver cancer, melanoma, colon cancer, lung cancer, cervical cancer, leukemia, Merkel cell carcinoma, lymphoma, and other malignancies.³³ Immunotherapy has entrenched itself as an innovative cornerstone, spanning from advanced stages to the use in the adjuvant and neoadjuvant settings to combat cancer.²⁸ Various forms of immunotherapy, such as adoptive cell transfer (ACT) and ICIs have achieved long-lasting responses. Although, it is crucial to note that their effectiveness varies among different cancer patients.³⁴

T lymphocytes play a critical role in directing the immune system's response against cancer by utilizing their specialized cytotoxic tendencies for precise targeting.³⁵ Progress in comprehending T cell biology has opened the door to successful approaches such as checkpoint inhibition, cellular therapy, and cancer vaccines, resulting in substantial advancements in clinical outcomes during the last five decades.³⁶ T cells undergo maturation and activation before becoming effector cells, which later use to locate and then treat cancer cells.³⁷ Breakthroughs in uncovering immune checkpoints such as CTLA-4 and PD-1 have paved the way in the contemporary immuno-oncology period and were recognized with Nobel Prize (2018) in Medicine or Physiology for Drs. Allison and Honjo.²⁸

T cells are central to cell-mediated immunity, and there have been significant advancements in genetically altering T cells, such as through chimeric antigen receptor (CAR) T cell therapy and T cell receptor (TCR) therapy.³⁸ These approaches have demonstrated promising results in clinical trials, underscoring their potential in combating malignant tumors and reducing their progression.³⁹ The immunotherapies comprising ICIs that target cytotoxic T lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) pathway have acquired impressive success in treatment of different types of cancers.⁴⁰ Therapeutic cancer vaccines have shown growing potential for use in personalized cancer immunotherapy.⁴¹ These cancer vaccines stimulate an adaptive immune response against various cancer antigens, ultimately resulting in tumor regression.^42,43 In the past, viruses were primarily explored as oncolytic agents (OVs), but their connection with immunotherapy has revealed. OVs are now considered as potent tools in the realms of gene and cancer immune therapy.⁴⁴

Monoclonal antibodies (MABs) have their roots in the concept of how B cell antibodies bind to particular type of antigens and to protect the body against foreign invaders. In the modern era, these antibodies have been approved and used for 30 different targets and are now regarded as form of immunotherapy for treating various types of cancers. Their exceptional ability of having low toxicity and to target specific molecules have established them as cornerstone of the pharmaceutical industry.⁴⁵

Recent years have witnessed transformative advancements in cancer immunotherapy, including adoptive cell therapy (ACT), immune checkpoint inhibition, and vaccines.⁴⁶ However, varying patient responses to these treatments have spurred a keen interest in understanding how T cell responses evolve with immune interventions. In the past decade, advanced single-cell technologies have provided unprecedented insight into the diverse cellular landscape within TME. Recently, the ability to link tumor characteristics with specific T cell receptor (TCR) antigen recognition has enabled in-depth exploration of tumor-reactive T cells.⁴⁷

Understanding T cells and immune system

The conventional categorization of immune system into innate and adaptive branches is somewhat simplistic, as these two forms of immunity often overlap and display interconnected roles.⁴⁸ Adaptive immunity comprises of B and T cells, wherein each lymphocyte presents a distinctive receptor that is specific and structurally distinct.⁴⁹ T cells are essential effectors of adaptive immunity, finely tuned to recognize and respond to specific pathogens through their antigen receptors, enabling targeted actions against infected or cancerous cells.⁵⁰ In the initial stages of an infection, pathogens trigger innate immune cells like macrophages, NK-cells and monocytes, as well as humoral factors such as complement.⁵¹ These pathways provoke a robust inflammatory response aimed at clearing the pathogens. In cases where the infection persists, antigen-presenting cells (APCs) ingest and process the pathogens, initiating presentation of antigen and triggering specific activation of B and T lymphocytes. Consequently, this prompts activation of effector mechanisms, such as cytokine release, production of immunoglobulins and clonal expansion.⁵²

The interplay and roles of adaptive and innate immune systems are crucial for combating cancer. Key players like classical effector CD4+ T helper Th1 and Th2 subsets play significant roles in generating anti-tumor immune responses. Th1 cells, through cytokine production such as TNF-α and IFNγ, promote cell-mediated killing, while Th2 cells, by releasing IL-4, activates humoral immunity, both are essential for combating tumors.⁵³ CD8-expressing cytotoxic T cells stand out as potent agents in combating cancer through immune response and are central to the success of current cancer immunotherapies. Cytotoxic CD8+ T cells are known as key players in immune system's defense against cancer, serving as its primary agents. In addition to enhancing long-lasting immune defence, they play pivotal role in removal of intracellular infections and malignant cells.^54,55

Recent studies have challenged the conventional understanding of T cell effector role, which categorizes CD4+ T cells, that serve as main producers of cytokines and CD8+ T cells as cytotoxic. These investigations have revealed that CD4+ T cells exhibit the capability to express cytolytic molecules such as perforin and granzymes, causing direct cytotoxic activity. This study suggests a more complex function for CD4+ T cells in immune reactions, including their role in targeting cancer cells for destruction as shown in Figure 1. Moreover, cytotoxic CD4+ T cells have been observed in various other conditions such as infections and autoimmune conditions, highlighting their wide-ranging importance in overseeing immune responses.⁵⁶

A study examining the impact of CD4+ T cell recognizing tumor antigens in cancer immunotherapy, specifically in patients who receive ipilimumab, an anti-CTLA-4 therapy, revealed intriguing findings.⁵⁷ Researchers retrospectively analyzed circulating T cells in such patients and observed an anticipated pharmacodynamic effect marked by increased absolute lymphocyte counts (ALCs). Remarkably, they further observed rise in ALCs after the initial dose and a subsequent increase in CD8+ T cell percentages within 8 and 14 weeks into treatment were linked to improved clinical responses and survival rates in melanoma patients. Surprisingly, a similar increase in CD4+ T cell percentages also correlates with positive clinical outcomes during this period.⁵⁸ Moreover, ICIs also target immune receptors that suppress immune activity, aiming to rejuvenate dysfunctional T cells, particularly CD8+ T cells. On the other hand, adoptive cell transfer involves using CD8+ T cells having genetically engineered receptors which are known as CARs. Ongoing clinical trials are exploring next-generation cytotoxic T cells engineered with modified or synthetic receptors. Additionally, combined treatment approaches hold promise for enhancing treatment outcomes and minimizing side effects.⁵⁹

Both strategies have transformed cancer treatment outcomes by increasing immune responses as shown in Table 1. The field of immuno-oncology has transformed cancer treatment by providing tailored and potent therapeutic choices, whether used independently or in conjunction with other protocols. This trajectory is anticipated to evolve and continue even further in years coming ahead.⁶⁰ In a study involving metastatic, castration-resistant prostate cancer (mCRPC) patients who receive granulocyte-macrophage colony-stimulating factor (GM-CSF) plus ipilimumab, various subsets such as CD4 + and CD8 + showed pharmacodynamics induction, but these variations weren't linked to outcomes. Instead, increased pre-existing CD4+ T cells and PD-1 in circulation were linked to improved overall survival.⁶¹ Additionally, if tumor antigens are recognized by CD4 + cells are significant for results, it suggests that antigens (tumor) must be constrained by MHC class II. Such expectation would imply a connection between expression of MHC class II and favorable clinical outcomes.⁶²

Table 1.

In vivo studies assessed antitumorigenic mode of action of different types of T cells against different types of cancer models.

Sr. no	Type (T cell)	Experimental model	Mode of action	Results	References
1.	Natural killer (NK) cells	Murine orthotopic H22 tumor model	↑ Secrete IFN-γ and CXCL16	Antitumor activity Survival rate increased notably	⁶³
2.	CAR T cells	Murine SCLC (Small cell lung cancer) model	Proinflammatory cytokines release ↑ IL-12 production ↑ IL-18 production	Enhanced antitumor efficacy	⁶⁴
3.	Cytotoxic T lymphocytes (CTLs)	Mouse melanoma B16F10 cells	Killing of cancer cells through perforin and granzyme- mediated cytotoxicity	Anticancer activity Increase the duration of survival	⁶⁵
4.	Helper T cells (Th cells) - Th1	BALB/c mice	Secrete cytokine ↑ IFN-γ ↑ Production of nitric oxide (NO) ↑ High levels of peroxynitrite	Tumor cell death by activation of the intrinsic apoptotic pathway	³⁷
5.	Follicular Helper T Cells (Tfh cells)	PDAC (Pancreatic ductal adenocarcinoma) mouse model	Secrete cytokines ↑ IL-21 ↑ CXCL13	Differentiation and maturation of B cells into plasma cells Production of tumor antigen-specific antibodies Long-term anti-tumor immune response	⁶⁶
6.	CD4-TCR and/or CD8-TCR (T Cell Receptor)	Rag1-deficient mice	Cytokine secretion ↑ Interleukin 1 (IL-1) ↑ Interleukin 6 (IL-6) ↑ Tumor necrosis factor-alpha (TNF-α)	Tumor regression Destroy the tumor vasculature and inhibit tumor angiogenesis through cytokine release Antitumor response	⁶⁷
7.	γδ T-cells	Mice model	Cytokine production ↑ Interferon-gamma (IFN-γ) ↑ Interleukin-17 (IL-17) Activate other immune cells Secrete immunosuppressive factors such as IL-10	Antimetastatic and antiangiogenesis Inhibit inflammation in TME	^68,69

Mechanism

Cancer immunotherapy operates through a three-step mechanism: Firstly, APCs (dendritic cells) recognize and break down antigens found within cancer cells, fragmenting them into antigenic peptides as shown in Figure 2. Subsequently, these peptides attach to human leukocyte antigens.^70,71 In the second phase, T cell activation hinges on the interplay of surface molecules termed as CD28 and B7 that are present on T cells and APCs, respectively.^36,72,73 Once cancer-specific T cells reach the tumor site, they identify and attack cancer cells by recognizing tumor antigens. T cell activation, which is crucial for this process, involves both co-stimulation and co-suppression alongside antigenic peptides.^74,75

Recently, growing fascination can be observed with innovative cancer immunotherapy methods designed to stimulate T cell-driven anti-tumor responses. Utilizing T cells to promote antigen-specific cytotoxicity has become a key strategy for using the body's immune system to treat cancer. This has led to explore new therapeutic strategies in cancer immunotherapy such as ICIs, ACT including cancer vaccine development and CAR T cell therapy, driven by understanding of cellular and molecular mechanisms.⁷⁶

Immune checkpoint inhibitors (ICIs)

Immunotherapies utilizing ICIs encompass monoclonal antibodies targeting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) as well as programmed cell death protein-1 and its ligand (PD-1 and PD-L1) as shown in Figure 3.⁷⁷ In 2011, the first immune checkpoint inhibitor, ipilimumab, was approved by US Food and Drug Administration (FDA).^78,79 Pembrolizumab, Ipilimumab and Nivolumab are monoclonal antibodies that were first approved for use as monotherapy. Their purpose is to interfere with T cell inhibitory signals, which in turn stimulates the immune system to fight tumors.⁸⁰

Checkpoint inhibitor targets

Cancer cells express various inhibitory immunoreceptors such as CTLA-4, PD-L1/L2, TIM3, LAG3, BTLA and TIGIT as shown in Figure 4. They are referred to as “immune checkpoints” and are also known as normal physiological regulators of immunological responses.⁸¹ T cells get “switch off signal” when immunological checkpoint receptors get attached to their complementary partner receptors over other cells such as cancerous cells. This cellular interaction stops the immune cells from getting rid of cancerous cells. ICIs stop the “switch off” signal and permit T cells to cause killing activity of tumor cells. ICIs such as anti-PD-L1/PD-1 anti-CTLA4 antibodies have demonstrated benefits in cancer treatment.⁸²

CTLA-4 pathway

Both CD28 and CTLA-4 play crucial roles as stimulatory receptors in regulating T cell activation and function. While CD28 facilitates T cell activation, CTLA-4 is pivotal in negatively regulating T cell responses.⁸³ CTLA-4 applies its inhibitory role through various mechanisms, such as suppressing proliferation of T cell, reducing IL-2 synthesis, impeding cell cycle advancement, and hindering differentiation of T cell.^84–86 Advanced Sezary syndrome or T cell lymphomas exhibit higher CTLA4-CD28 fusion so anti-CTLA4 cancer immunotherapy targets this fusion of CTLA4-CD28.^87,88 CTLA-4 plays crucial role in inducing self-tolerance as well as regulating immune responses.^83,89 Tremelimumab (NCT01008358), an antibody against CTLA-4 prevents T cell attenuation and enhances the expression of various cytokines such as interferon gamma (IFNγ) and interleukins IL-6 to provide anti-cancerous immunity against renal cancer, melanoma and non-small cell lung cancer (NSCLC).⁹⁰

LAG3 pathway

Activated immune cells such as Treg cells, T cells, dendritic cells and natural killer cells produce CD-4 like molecule known as LAG3, like PD-1 it negatively hinders T-cell activation.⁹¹ Relatlimab (BMS-986016) is LAG3 inhibitor that is developed by Bristol-Myers Squibb and is used to treat melanoma in association with Nivolumab. Anti-LAG3 antibody named as REGN3767 that is labeled with zirconium-89 (⁸⁹Zr-REGN3767) is currently used for tumor imaging.⁹²

TIGIT pathway

In order improve immune surveillance against different types of tumors, a novel class of immunoreceptor checkpoint, TIGIT is being used.⁹³ Basically, TIGIT is member of T-cell immunoreceptor (PVR/ poliovirus receptor family). Two ligands for TIGIT are CD112 (PVRL2) and CD155 (PVR: higher affinity towards TIGIT). TIGIT possesses inhibitory action on natural killer (NK) and T cells and hinders T cell function by enhancing IL-10 secretion of DCs by the way of reverse CD155 signaling.⁹⁴ Anti PD-L1/PD-1 and anti TIGIT antibodies have very effective outcomes in preclinical models by activating T-cells. So, all the immunotherapies that are concerned with TIGIT inhibitors either in form of monotherapy or in the association of anti PD-L1/PD-1 are in phase I clinical trial. AB154, BMS-986207 and MTIG7192a, are referred to as anti-TIGIT therapies that are under clinical trials (phase I) in association with Nivolumab (PD-1), Atezolizumab (anti PD-L1) and AB122 (PD-1) whereas MK-7684 monotherapy and OMP-313M32 are also in phase I clinical trial.⁹⁰

TIM-3 pathway

TIM-3 is classified as a transmembrane protein that is presented over the surface of various immune cells such as CD8 + T cells, CD4 + T cells, and myeloid cells. Galactin-9 (GAL-9) is known as the ligand of TIM-3 that causes T-cell apoptosis. TIM-3 has also been involved in overexpression of Th17 and Th1 cytokines.⁹⁵ There are various anti-TIM-3 mAbs that are in under trial such as MGB453 is under clinical trial for advanced type of malignancy indications (NCT02608268).⁹⁶

PD-L1/PD-1 pathway

Immunotherapies targeting the PD-1/PD-L1 axis have shown remarkable efficacy against a diverse range of human malignancies.⁹⁷ PD-1 is a member of CD28 family and is predominantly found in various immune cell types, particularly activated CD4+ T cells, CD8+ T cells, and B cells present in peripheral tissues.⁹⁸ The programmed death protein 1 (PD-1) and its corresponding ligand, programmed death-ligand 1 (PD-L1), play significant roles in regulating the effectiveness of T-cell immune responses by exerting negative control. Drugs that target PD-L1/PD-1 pathway are used to block immune checkpoints, showing promise in eliciting positive clinical outcomes in various cancer types.⁹⁹ Various pathways regulate PD-1/PD-L1 expression as shown in Figure 5.

Pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) are considered as main extrinsic factors that regulate PD-L1 expression.^100,101

Clinical application (PD-L1/ PD-1 blockade therapies)

Anti-PD-1/PD-L1 antibodies interrupt immune checkpoints and block PD-L1/PD-1 pathway and thus reactivating T cells to target tumors. The breakthrough in cancer immunotherapy by using PD-1/PD-L1 blockade sets a model for translating scientific discoveries into clinical practice.⁹⁷ Numerous antibodies targeting PD-1 have been developed thus far. The FDA approved cemiplimab (Libtayo) in September 2014, pembrolizumab (Keytruda) in December 2014, and nivolumab (Opdivo) in September 2018 respectively. Pidilizumab AMP-514, AMP-224 and PDR001 are currently undergoing experimental development.^79,102–104

Over the years, there has been extensive research into the combined utilization of PD-1 and CTLA-4 inhibitors. These studies have demonstrated that they possess complementary effects in activating the anti-cancer immune response. Moreover, when compared to blocking individual checkpoints, this combination has shown improved clinical efficacy across various cancer subtypes as shown in Table 2.^105–107 The combination of nivolumab (an IgG4 anti-PD-1 monoclonal antibody) and ipilimumab (a totally humanized IgG1 antiCTLA-4 monoclonal antibody) is widely recognized as a leading treatment regimen. It has been investigated thoroughly in over 100 clinical trials, constantly demonstrating effective outcomes.¹⁰⁸

Table 2.

FDA approved anti-PD-1, anti-PD-L1 and CTLA-4 antibodies.

Target	Associated Therapies	Trade Name (Company Name)	Cancerefficacy and targetedcancer	Approval year	Clinical efficacy and Results	References
PD-1	Pembrolizumab	Keytruda® (Merck Co., New Jersey, USA)	Advanced BRAFmut melanoma	2014	Inhibits binding of PD-L1 and PD-L2 to PD-1 T cell reactivation Upon activation, T cells secrete a potent arsenal of cytokines, like IFN-γ and TNF-α Anti-tumor effects such as direct cytotoxicity and improves overall survival (granzyme and perforin release)	¹¹⁷
			Improves overall survival in Non-small cell lung cancer	2015		^118–120
			Head-and-neck squamous cell carcinoma	2016		^121,122
			Improves overall survival inHodgkin lymphoma, Non-squamous NSCLC, Urothelial carcinoma, Unresectable or metastatic solid tumors, Gastric or gastroesophageal junction cancer	2017		^123–130
			Cervical cancer, Merkel cell carcinoma, Hepatocellular carcinoma, Squamous NSCLC, Primary mediastinal large B-cell lymphoma	2018		^131–137
			Renal cell carcinoma, Endometrial carcinoma, Squamous cell carcinoma of the esophagus, Small cell lung cancer	2019		^138–141
			Gastric or gastroesophageal junction (GEJ) adenocarcinoma, High-risk, early-stage triple-negative breast cancer	2020		^142–145
			Advanced/Metastatic PD-L1–High NSCLC	2021		¹⁴⁶
	Nivolumab	Opdivo®(Bristol-Myers Squibb, New York, USA)	Advanced melanoma	2014	Durable anticancer immune response and improves overall survival Ensuring proper immune regulation Fine-tuning T cell function	^147–150
			Squamous NSCLC, Renal cell carcinoma, Non-squamous NSCLC	2015		^151–153
			Head-and-neck cancer, Hodgkin lymphoma	2016		^154–156
			Hepatocellular carcinoma, Colorectal cancer, Urothelial carcinoma	2017		^157–160
			Small cell lung cancer	2018		^161,162
			Esophageal squamous cell carcinoma, Metastatic NSCLC	2020		^163–165
			Esophageal or gastroesophageal junction cancer	2021		^166,167
PD-L1	Atezolizumab	Tecentriq® (Roche, Basel, Switzerland)	NSCLC, Urothelial carcinoma	2016	Disrupts the PD-L1/PD-1 signaling mechanism Stimulates T cell response Triggers T cell activation through ICIs Hinders PD-1/PD-L1 binding	^168–170
			Bladder cancer	2017		¹⁷¹
			Triple-negative breast cancer	2019		^172,173
			Unresectable hepatocellular carcinoma	2020		^174,175
	Avelumab	Bavencio® (Pfizer, New York, USA and Merck, USA)	Merkel cell carcinoma, Urothelial carcinoma	2017	Blocking the PD-L1 checkpoint Stimulating immune system for cancer treatment Tumor defense and improves overall survival	^176–179
	Avelumab	Bavencio® (Pfizer, New York, USA and Merck, USA)	Renal cell carcinoma	2019		^180,181
	Durvalumab	Imfinzi® (AstraZeneca, Cambridge, UK)	Bladder cancer	2017	Empowers T cells to mount a more potent attack against tumors Triggers a more robust immunological response to control tumor growth Slows or halts the expansion of cancerous cells	^182,183
			NSCLC	2018		^184,185
			SCLC	2020		^186,187
CTLA-4	Ipilimumab	Yervoy® (Bristol-Myers Squibb, New York, USA)	Metastatic Colorectal Cancer	2017	CTLA-4 blockade Immune activation Anti-tumor response T-cell proliferation	^188,189
			Renal cell carcinoma	2018		^190,191
			Hepatocellular carcinoma	2020		^192,193
	Tremelimumab	Tremelimumab-actl; IMJUDO® (AstraZeneca, Cambridge, UK)	Metastatic non-small cell lung cancer (mNSCLC), Unresectable hepatocellular carcinoma (uHCC)	2022	CTLA-4 blockade Checkpoint inhibitor Tumor targeting Immune activation and improves overall survival	^194–196

FDA approved nivolumab in 2014, marketed as Opdivo and also referred to as BMS-936558 and MDX1106, for treating metastatic or unresectable melanoma.¹⁰⁹ Nivolumab is a monoclonal antibody having strong affinity for PD-1, disrupting its interaction with PD-L1 ligand.¹¹⁰ Nivolumab was approved in March 2015 by FDA to treat metastatic NSCLC squamous cells.¹¹¹ Apart from melanoma and NSCLC, nivolumab has shown efficacy in several other cancers such as Hodgkin's lymphoma and hepatocellular carcinoma.^112,113

Cemiplimab is an anti-PD-1 antibody that is designed particularly for treating cutaneous squamous cell carcinoma (CSCC).¹¹⁴ It has recently been approved from FDA, making it first checkpoint therapy tailored for this disease. In a trial phase 1, evaluating cemiplimab therapy in CSCC patients, a lasting response was noticed, with no disease recurrence noted beyond 16 months post-treatment.¹¹⁵

Atezolizumab, commercially known as Tecentriq or MPDL3280A, is a human IgG1 monoclonal antibody that is derived from phages, featuring Fc fragment and its mechanism involves inhibition of PD-L1 on tumor surfaces, demonstrating potential for efficient tumor suppression. By using genetic engineering method, modifications to the Fc fragment of atezolizumab enable the avoidance of antibody-dependent cell-mediated cytotoxicity (ADCC) effects.¹¹⁶

Limitations and side adverse effects of ICIs

Despite the success of ICIs, resistance limits the number of patients who can achieve a lasting response, and so immune-related adverse events (irAEs) complicate the treatment. ICIs cause break in the immune balance of the body and thereby reduce T-cell tolerance, and ultimately leading to the production of a series of irAEs.¹⁹⁷ The mechanism of irAEs is still unclear. Currently, irAEs are believed to be related to alterations in the function of the body's autoimmune system, including the breaking of autoimmune tolerance or the body then becoming more sensitive to antigen recognition and attacking its own tissues.¹⁹⁸ IrAEs are common and have been reported to occur in 90% of patients treated with anti-CTLA-4 and 70% of patients treated with anti-PD-1/PD-L1.¹⁹⁹ Multiple mechanisms have been proposed to explain the occurrence of irAEs, such as the production of autoantibodies, T-cell infiltration, and the mediation of inflammatory cytokines such as IL. The Cutaneous irAEs are the most common form is cutaneous irAEs that is followed by endocrine irAEs. If we predict and monitor the risk of irAEs in patients through related biomarkers and take timely and effective preventive and intervention measures to prevent the deterioration of adverse events, it is of great significance to ensure the safety of the subjects and the smooth conduct of clinical trials. The current treatment for irAEs primarily involves the use of corticosteroids, immunosuppressants, corticosteroids, and cytokine antagonists.²⁰⁰

Biomarkers in cancer immunotherapy

Cancer immunotherapy has revolutionized treatment of advanced cancer patients, offering long-lasting and remarkable clinical benefits in different types of cancers. However, a significant challenge persists in identifying particular biomarkers to effectively predict a patient's response to specific type of treatment. While certain tests for cancer immunotherapy are well-established and are associated to approved therapies, others are still in the process of emerging and undergoing different stages of clinical and translational research.²⁰¹ Biomarkers for cancer immunotherapy are described in the following Table 3.

Table 3.

Biomarkers for cancer immunotherapy.

Sample	Biomarker	Clinical Significance	References
Tumor Tissue	PD-L1	Enhanced activity in cancer cells is linked to a favorable clinical outcome while using anti-PDL-1/PD-1 antibodies for treatment.	^202–207
	TMB	A high tumor mutational burden (TMB) is linked to a better clinical outcome to ICIs.	^208–211
	MMR	A deficiency in MMR, irrespective of the type of tumor, is associated with a positive clinical response to pembrolizumab.	^212–215
	TIL	A favorable prognosis is associated with the presence of CD8+ T lymphocytes infiltrating tumor.	^216–219
	Tregs/ MDSCs	A poor prognosis is linked to the presence of myeloid-derived suppressor cells (MDSCs) and tumor-infiltrating regulatory T cells (Tregs).	^220–223
Peripheral Blood	Neutrophils/ leukocytes	An elevated Neutrophil-to-Lymphocyte Ratio (NLR) is linked to an unfavorable treatment outcome.	^224–227
	Low % of lymphocytes	Exclude patients from immunotherapy if their lymphocyte count is below 15%.	^228–230
	LDH	Higher pretreatment levels are associated with a poor overall survival outcome.	^231–234
	CRP	Elevated levels of CRP are linked to a higher likelihood of experiencing Overall Survival (OS) risks.	^235–238
	miRNA	The clinical outcomes are linked to the expression of multiple miRNAs.	^239,240
	Tregs/ MDSCs	Improved prognosis correlated with a reduction in the circulating levels of Tregs and MDSCs following treatment.	^241–243
	Ki-67 expression	Elevated Ki-67 expression within PD1+ CD8+ T cells is linked to a favorable treatment response.	^244–248
Feces	Microbiome	In melanoma patients, the presence of Ruminococcaceae/ Faecalibacterium and Akkermansia muciniphila in NSCLC and RCC is linked to a favorable clinical response treated with anti-PD-1 antibody treatment.	^249–254

PD-1, programmed cell death receptor-1; PD-L1, ICIs, immune checkpoint inhibitors; programmed cell death-1 ligand 1; TIL, tumor-infiltrating lymphocyte; TMB, tumor mutation burden; MMR, mismatch repair; Treg, regulatory T cells; NLR, neutrophil-to-lymphocyte ratio; MDSC, myeloid-derived suppressor cells; NSCLC, non-small-cell lung carcinoma; CRP, C-reactive protein; OS, overall survival; LDH, lactate dehydrogenase; miRNA, micro ribonucleic acid; RCC, renal cell cancer.

It is necessary to identify and develop biomarkers as shown in Table 3 that can further forecast patient responses to immunotherapy and their overall prognosis. While there are many factors from peripheral blood, tumor tissue, and other sources that could impact how individuals respond to cancer immunotherapy, their prognostic and predictive capabilities have yet to be verified through randomized and rigorous prospective clinical trials. Moreover, predicting responses using a single biomarker is challenging because of intricate interplay between human immune system and tumor. Consequently, a comprehensive evaluation of spatial and dynamic aspects of tumor immunity has paramount importance for the successful implementation of cancer immunotherapy.²⁵⁵

Immunotherapeutic strategies targeting T cells

Adoptive T Cell therapy

Over the past decade, two forms of immunotherapy have emerged as particularly effective in cancer treatment: using ICIs to enhance the body's natural anti-tumor response, and employing ACT to administer specialized immune system cells targeted at fighting tumors as shown in Figure 6.²⁵⁶ The application of ACT using tumor-infiltrating lymphocytes (TILs) has demonstrated considerable potential in addressing solid tumors that are either unresectable or metastatic.²⁵⁷ This procedure includes removing the tumor, isolating TILs, selecting for TILs with autologous tumor reactivity ex vivo, rapidly expanding them, and then reintroducing the expanded T cell product back into the patient.²⁵⁸ The primary objective of utilizing ACT is to induce a potent immune attack on tumors by infusing T cells that are modified outside our body. ACT strategies employ engineered and modified T cells to eliminate tumors. Firstly, extract tumor-specific T cells that are present naturally within existing tumor masses (known as TILs). Then, genetically modifying T cells that are derived from blood to attack specifically tumor cells. In each case, T cells are modified outside the body, which undergo multiplication, and then subsequently reintroduced into patient's body who has undergone lymphodepletion.²⁵⁶

T cells can easily be amplified either from naturally occurring tumor-specific T cells (CD8+ T cells) found within tumor infiltrating lymphocytes (TIL), or from circulating CD8+ T cells (autologous) that have been genetically modified. These engineered T cells possess tumor-specific antigen receptors, such as T cell receptors (TCRs) or CARs that are derived from cultured T and B cell clones, respectively.²⁵⁹

CAR T cell therapy

Recently, advancements in gene-engineering technology have enabled the reliable production of T cells to combat cancer. This process is carried out by transferring antigen receptors into T cells that further have been activated within a controlled laboratory environment, such as Chimeric Antigen Receptor T cells (CAR-T) and TCR engineered T cells (TCR-T) as shown in Figure 7.^260,261 Furthermore, CAR T cell therapy stands as a transformative advancement in field of immunotherapy, triumphing against hematological malignancies and increasingly, autoimmune disorders. After a decade of relatively modest results for solid tumors, recent clinical trials and patient reports have also started to yield promising outcomes in glioblastoma (GBM) and other challenging solid tumor entities.²⁶² One of the most promising targets for CAR T cell therapy in GBM is IL13Rα2, which is a membrane-bound protein expressed in over 75% of GBMs that is associated with activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) pathway.^263–265 IL13Rα2 has long been recognized as a promising an attractive candidate for CAR T-cell targeting.²⁶⁶

Gene editing technologies such as CRISPR are currently integrated into CAR T cell design to enhance safety and efficacy. By using CRISPR-Cas9, researchers can easily achieve precise “knock-in” of CAR genes at specific genomic loci, such as T-cell receptor alpha chain (TRAC), which increases CAR expression as well as anti-tumor activity thereby reducing risks associated with random integration methods. Moreover, CRISPR enables multi-gene editing, allowing the simultaneous modification of several targets in T cells to optimize their functionality against different tumor types, thus addressing challenges in solid tumor therapies and improving overall treatment outcomes.²⁶⁷ Additionally, CRISPR-Cas9-induced multiplex knockout of inhibitory molecules potentiates enhanced CAR T-cell expansion and persistence that may allow for circumvention of T-cell-intrinsic as well as extrinsic resistance mechanisms operative in both hematopoietic and non-hematopoietic malignancies.²⁶⁸

Cancer vaccines

The origin of cancer vaccination can be traced back to the observation that some tumors exhibit regression in individuals who are undergoing acute infections.²⁶⁹ Vaccines targeting cancer show significant potential for immunotherapy in treatment of various solid tumors.²⁷⁰ Therapeutic cancer vaccines aim to trigger tumor shrinkage, eliminate any remaining cancer cells, create enduring anti-tumor immune memory, and minimize nonspecific or adverse responses.²⁷¹ Successful therapeutic vaccination against tumors relies on several key principles: efficient delivery of abundant, high-quality antigens to dendritic cells (DCs), effective stimulation of DCs, initiation of persistent cytotoxic T lymphocyte (CTL) as well as CD4+ T helper cell responses, infiltration of TME, ensuring maintenance and durability of immune response.²⁷² The origin of cancer vaccination can be traced back to the observation that some tumors exhibit regression in individuals who are undergoing acute infections.^269,273 Vaccines targeting cancer show significant potential for immunotherapy in treatment of various solid tumors.²⁷⁰ Therapeutic cancer vaccines aim to trigger tumor shrinkage, eliminate any remaining cancer cells, create enduring anti-tumor immune memory, and minimize nonspecific or adverse responses as shown in Figure 8.²⁷¹ Successful therapeutic vaccination against tumors relies on several key principles: efficient delivery of abundant, high-quality antigens to dendritic cells (DCs), effective stimulation of DCs, initiation of persistent cytotoxic T lymphocyte (CTL) as well as CD4+ T helper cell responses, infiltration of TME, ensuring maintenance and durability of immune response.²⁷²

Manufacturing peptide-based vaccines is relatively straightforward, yet enhancing their effectiveness often requires pairing them with powerful immune adjuvants. Additionally, the potential beneficiaries of a particular peptide vaccine are limited by their specific human leukocyte antigen (HLA) haplotype.²⁷⁴ Majority of peptide-based vaccines rely on epitope peptides to activate either CD4+ T helper cells or CD8+ T cells, directing them to identify and then attack tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) as shown in Table 4.²⁷⁵

Table 4.

Tumor specific and tumor associated antigens in different types of cancers.

Tumor	Tumor- specific antigens	Tumor associated antigens	References
Oesophageal cancer	URLC10	CEA, KOC1, TTK, HSP105, VEGFR	^276–282
Lung cancer	Lengsin, KIF20A, MAGE-A, PRAME, NY-ESO-1, URLC10, CDCA1	CDC45L, Survivin, STEAP1, TERT, HER2, IDO, KOC1, MUC1, SOX2, CEA, TTK, VEGFR	^283–291
Breast cancer	PLAC1, KIF20A, URLC10, E6/E7a (HPV), m-P53, CDCA1	CEA, MUC1, DEPDC1, TAL6, Mam-A, ErbB2, FBP, TTK, HER2/neu	^275,292
Pancreatic cancer	KIF20A	CEA, VEGFR, Survivin	^293–295
Prostatic cancer	CDCA1, TARP, SSX-2, PSMA	EpCAM, HPN, KLK4, AR LBD, PSCA	^296–300
Melanoma	MAGE-A, E7a (HPV), NY- ESO-1, PRAME	MART-1, telomerase, Survivin, Melan-A, TBVA, VEGFR, Tyrosinase	^301–304
Colorectal cancer	E6/E7a (HPV), MCAK	AGR2, HSP105, MTA1, Survivin, VEGFR, TOMM34, HERV-H, CEA	^305–307

Up-regulated gene in lung cancer 10, URLC10; Cell division associated 1, CDCA1; Kinesin family member 20A, KIF20A; Melanoma-associated antigen-A, MAGE-A; New York esophageal squamous cell carcinoma 1, NY-ESO-1; Preferentially Expressed Antigen in Melanoma, PRAME; Placenta-specific protein 1, Plac1; Human Papillomavirus, HPV; Prostate-specific membrane antigen, PSMA; T-cell receptor alternate reading frame protein, TARP; Mitotic centromere-associated kinesin, MCAK; Carcinoembryonic antigen, CEA; Heat shock protein 105, HSP105; KH domain-containing protein overexpressed in cancer 1, KOC1; threonine tyrosine kinase, TTK; Vascular endothelial growth factor receptor, VEGFR; cell division cycle 45 like, CDC45L; Human epidermal growth factor receptor 2, HER2; Indoleamine 2,3-dioxygenase, IDO; Mucin 1, MUC1; Six-transmembrane epithelial antigen of prostate-1, STEAP1; Telomerase reverse transcriptase, TERT; DEP domain containing 1, DEPDC1; Erythroblastic oncogene B 2 ErbB2; Folate binding protein, FBP; Tumor-associated antigen L6, TAL6; Epithelial cell adhesion molecule, EpCAM; Androgen receptor ligand-binding domain, AR LBD; Kallikrein related peptidase 4, KLK4; Prostate stem cell antigen, PSCA; Hepsin, HPN; Melanoma-associated antigen recognized by T cells, MART-1; Melanocyte Antigen, Melan-A; Tumor-blood vessel-associated antigens, TBVA; Human anterior gradient-2, AGR2; Human endogenous retroviruses, HERV; Metastasis-associated protein 1, MTA1; RING finger protein 43, RNF43; Translocase of the outer mitochondrial membrane 34, TOMM34.

Sipuleucel-T, the first therapeutic cancer vaccine, has been approved by FDA. This vaccine is composed of autologous peripheral blood mononuclear cells such as dendritic cells, that are loaded with prostatic acid phosphatase antigen which further fused with GM-CSF, then finally activates immune cells.^308,309

Virus-based vaccines present a promising approach for vaccine development, as their genetic material (DNA or RNA) can activate dendritic cells via pattern recognition receptors.^310,311 Despite of therapeutic cancer vaccines, intravesical immunotherapy, such as the administration of Mycobacterium bovis bacillus Calmette–Guérin (BCG), that is approved for the treating bladder cancer.³¹² In 2015, T-VEC was approved as a therapy for unresectable melanoma. T-VEC, derived from the herpes virus and engineered to produce GM-CSF, is an oncolytic viral vaccine.^274,313 OVs are versatile biotherapeutic agents that exhibit multifaceted capabilities, including replication within tumor cells to induce their destruction and the enhancement of immune responses through the release of immunostimulatory molecules from lysed cells.³¹⁴ Virus-based vaccines present a promising approach for vaccine development, as their genetic material (DNA or RNA) can activate dendritic cells via pattern recognition receptors.^310,311 Despite of therapeutic cancer vaccines, intravesical immunotherapy, such as the administration of Mycobacterium bovis BCG, that is approved for the treating bladder cancer.³¹² In 2015, T-VEC was approved as a therapy for unresectable melanoma. T-VEC, derived from the herpes virus and engineered to produce GM-CSF, is an oncolytic viral vaccine.^274,313 OVs are versatile biotherapeutic agents that exhibit multifaceted capabilities, including replication within tumor cells to induce their destruction and the enhancement of immune responses through the release of immunostimulatory molecules from lysed cells.³¹⁴

Cytokine therapy

Cytokines comprise of several interleukins named as IL-4, IL-7, IL-9, IL-2, IL-21, and IL-15 as shown in Figure 9. IL-2 and IL-7 are two of them that have been utilized extensively and for a long time to stimulate T cell growth and proliferation. Cytokines called interleukins IL-2 and IL-7, which target several facets of T-cell responses, have been employed to combat cancer.³¹⁵ IL-2 plays significant role in the regulating CD4⁺ based T-cell immunity. It also promotes survival and polarization of the T_REG cells, T_H1, T_H2, and T_H9, simultaneously inhibiting the generation of T_H17 cells and follicular helper T (T_FH) cells by regulating STAT5 downstream signaling.^316,317

Extensive investigation has been conducted on IL-2 administration within adoptive T-cell therapy, which encompasses autologous CAR T cells and TILs.³¹⁸ IL-7 is crucial in the maturation of αβ and γδ T cells. While αβ T cells can be somewhat rejuvenated by introducing anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl2) through genetic modification, γδ T cells do not show similar rescue, indicating the indispensable nature of IL-7 signaling for thymocyte survival.^319,320 Extensive investigation has been conducted on IL-2 administration within adoptive T-cell therapy, which encompasses autologous CAR T cells and TILs.³¹⁸ IL-7 is crucial in the maturation of αβ and γδ T cells. While αβ T cells can be somewhat rejuvenated by introducing anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl2) through genetic modification, γδ T cells do not show similar rescue, indicating the indispensable nature of IL-7 signaling for thymocyte survival.^319,320

Relationship of T cell based immunotherapy with different types of cancers

Breast cancer

Breast cancer persists as a multifaceted and widespread health issue impacting millions of people globally.³²¹ Immunotherapy, utilizing ACT or immune checkpoint inhibitor, has sparked renewed hope for sustained outcomes in patients with advanced solid and hematological tumors. Yet, its full potential in treating breast cancer is still being explored.³²² Several strategies in immunotherapy have been explored for breast cancer, including the use of antibodies that target tumor such as bispecific antibodies, vaccination, adoptive T cell therapy, and ICIs like anti-PD-1.³²³ TAAs in BC (breast cancer) such as Lewis Y, FR-α, HER2, Muc1 and mesothelin have been investigated as CAR-T targets both in animal models and in vitro.³²⁴ T cells constitute a significant portion of the immune presence within various solid tumors, including those in the breast, playing a crucial role in combating cancer cells. Activated cytotoxic T lymphocytes (CTLs) can easily carry out their roles by releasing cytolytic substances such as granulysin and granzymes, or by producing inflammatory cytokines such as TNF-α and IFN-γ.^59,325,326

CD8+ T cells serve as an effective role within both tumor immune microenvironment (TIME) and TILs as shown in Figure 10.³²⁷ The TIME exerts significant influence on tumor advancement, treatment efficacy, and patient prognosis across various cancers, notably breast cancer.^328–330 TILs possess significant role in TIME, in quantity and variety of lymphocytes within TIL population of a tumor are strongly linked to prognostic indicators in breast cancer.^331,332

Lung cancer

World Health Organization (WHO) classifies lung tumors into two categories; NSCLC, showing 80–85% of all lung cancer cases, and small cell lung cancer (SCLC), constituting 15% incidences.^333–335 T cells influence progression, genesis and metastasis of lung cancer through cytokine-mediated effects.³³⁶

CAR-T cells show promising effect and hope for NSCLC as novel immunotherapy agent.³³⁷ The Th1 cell is regarded as the first subset that was discovered in CD4+ T cells which releases IL-2, tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) that further contribute to carry out antitumor immune activity in lung cancer.³³⁸ Apart from Th1 cells, various other subpopulations particularly Th17 cells (producing IL-17) and Th9 cells (producing IL-21 and IL-9) have been involved in lung cancer.^339,340 The TILs quantity has proved positive that correlates with prognosis in case of lung cancer, and make an ideal candidate suitable for carrying out ACT using TILs.^341,342

Colorectal cancer

Colorectal cancer ranks as third most common cancer diagnosis worldwide.³⁴³ In colorectal cancer's TME, IFN-γ is predominantly produced by NKT cells, CD8+ T cells infiltrating the tumor, and NK cells. IFN-γ can subsequently induce increased infiltration of CD8+ T cells and NK cells into (TME). Patients with colorectal cancer have been observed to experience a reduction in expression of various genes that are related to IFNγ signaling.³⁴⁴ The role of cytotoxic T lymphocyte immunotherapy to improve prognosis in case of colorectal cancer patients is evident, especially for those having heightened T cell infiltration within TME, demonstrating its tendency to improve responses for select individuals.³⁴⁵ Research into CAR T-cell therapy for colorectal cancer shows the use of T cells (genetically engineered) that are equipped with CARs, showing potential efficacy. This process is carried out by extraction, amplification, and reintroduction of the patient's own T cells, particularly after genetic modifications to target and release tumor antigens.³⁴⁶ Monoclonal antibody therapy serves as the predominant form of immunotherapy which is utilized for treating gastrointestinal cancers. For gastrointestinal malignancies, FDA has approved four monoclonal antibody therapies such as rituximab, bevacizumab, panitumumab, and trastuzumab, along with cetuximab.^347–349

Liver cancer

Immunotherapy represents a hopeful strategy for treatment of different types of cancer such as hepatocellular carcinoma (HCC).³⁵⁰ Recently, ICIs have transformed cancer treatment and garnered heightened attention for managing HCC. In 2020, the pairing of atezolizumab with bevacizumab (an anti-vascular endothelial growth factor therapy) demonstrated enhanced overall survival compared to sorafenib, leading to FDA approval as a frontline therapy for advanced HCC patients.³⁵¹ Exploration of immunotherapy, using ICIs (PD-L1, PD-1 and CTLA-4), customized cytokines, CAR-T and vaccines, is on the rise in liver cancer treatment, offering new avenues of hope for patients with HCC.^352–354

Leukemia

AML (Acute Myelogenous Leukemia), characterized by its heterogeneous nature, is a malignancy affecting the hematopoietic system.³⁵⁵ The condition arises from genetic mutations leading to the excessive growth of cancerous cells originating from precursor cells within the myeloid lineage.³⁵⁶ Clinical trials utilizing CAR-T cells have been conducted in patients experiencing relapsed AML, with one of the initial positive outcomes reported in 2019.³⁵⁷ When stimulated, CAR-T cells have the ability to trigger apoptosis in cancer cells lacking the target antigen through the Fas and FasL pathway, enabling them to exert effector functions within a tumor exhibiting varying antigen expression patterns.³⁵⁸ Upon activation, CAR-T cells possess tendency to release pro-inflammatory cytokines, thereby increasing immune response against cancer as shown in Figure 11.³⁵⁹

Bispecific antibodies (BsAbs) are known as molecular biotherapies that directly bind to and then activate effector T-cells and after it, drive them to B-cell antigens, causing a similar cellular-dependent cytotoxicity.³⁶⁰ T lymphocytes having heterogeneous TCRs are capable of recognizing HLA-peptide complexes present on cancerous cells and then transmit antigen-stimulating signals via phosphorylation of immune tyrosine-based activation motif (ITAM), and later activate the immune effects of immune cells such as T cells to kill tumor cells.³⁶¹

Prostate cancer

Prostate cancer (PCa) is one of the main causes of cancer-related death in men.³⁶² In the current ‘new era’ of cancer immunotherapy, clinical trials have been carried out to verify the potential for using CAR T cells to identify and eliminate malignant cells as shown in Figure 12.³⁶³

The identification of prostate TAAs is the first step towards developing an effective CAR-T cell therapy. An ideal antigen should be constitutive and specifically expressed by cancer cells to enable CAR-T cells to develop a cancer-specific immunologic response, thus sparing healthy tissue.^364,365 Preclinical studies show that combination with standard therapies, such as androgen deprivation therapy, radiotherapy or chemotherapy, can be used to enhance the efficacy of CAR T cells against prostate cancer.³⁶⁶

Conclusion and future perspectives

Decades of dedicated research have unleashed the immense potential of stimulating the natural defense system to treat cancer of different types. T cell-based immunotherapies serve as a revolutionary force that offers a targeted and powerful approach to combat cancer. ICIs and ACT are two main pillars that support this revolution. ICIs encompasses on removing “brakes” on immune system, unlocking the body's pre-existing T cell based anti-tumor response. On the other hand, ACT uses patient's T cells that are genetically engineered which further used to identify and directly attack tumor cells. Recently, these therapies have acquired efficient and remarkable results with CAR T-cell therapy, conducting potential cures for previously existing untreatable blood cancers. Likewise, ICIs such as PD-1 inhibitors, have shown efficacy across a diverse range of cancers, thus offering an iota of hope to cancerous patients. In conclusion, it can be inferred that it has transformed the paradigm from cytotoxic therapies that target both healthy and cancerous cells to a more personalized approach that enhances the body's immune system to combat cancer.

The horizon of T cell-based immunotherapy is teeming with exciting possibilities. Clinical investigations are actively focused on surpassing current limitations. Novel CAR designs incorporating various co-stimulatory molecules or targeting elements hold significant impact reduced toxicity and increased efficacy but manufacturing of CAR T cells is expensive due to complex, patient-specific nature of the therapy. Moreover, prolonged production times also delay patient access to treatment. Gene editing techniques such as CRISPR-Cas9 provide potential to engineer T cells having increased tumor-killing tendencies and persistence within body. Exploring combination therapies, such as utilizing T cell based therapies with various other modalities like radiation or chemotherapy could lead to synergistic effects as well as result in improved overall survival. For instance, the combination of cisplatin (CDDP) and radiotherapy has shown enhanced antitumor effects across various cancers, Clinical observations suggest that combination therapies not only enhance tumor regression but also improve safety profiles by mitigating adverse effects typically associated with high-dose CAR T-cell therapies. The main challenges of T cell-based immunotherapy for treatment of cancer include antigen escape, toxicity, limited specificity, restricted tumor infiltration and trafficking and various side effects. While challenges persist, ongoing development and research attempts hold promise and hope for further refining this novel and revolutionary approach. With continued advancements, these T cell-based therapies have potential to reconstruct cancer from a dreaded disease into potentially curable and even manageable condition.

Footnotes

Author contributions

MA wrote the manuscript and pictorial work. SA planned, supervised, edited the manuscript and analyzed the data. MS supervised, provided data for mechanistic study and analyzed the data. MZ analyzed the data and assisted in write up. SN assisted in write up and proofread the data. LN assisted in write up and analyzed the data. MAJ assisted in write up.

Data availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

As no animal is being used/sacrificed in present study, ethical approval was not applicable.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Shaukat Ali

Muhammad Abdullah Javed

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