Holistic Understanding of the Current Landscape, Challenges, and Potential Advancements in the Integration of Immunotherapy with Traditional Cancer Treatments: A Narrative Review

1. Introduction

Cancer is a complex and heterogeneous group of diseases characterized by the uncontrolled proliferation of cells that can invade other parts of the body, leading to significant mortality worldwide [1]. It arises due to genetic mutations, exposure to carcinogens, viral infections, and lifestyle factors, all of which contribute to the dysregulation of normal cellular mechanisms [2,3]. Cancer cells evade the body’s natural control mechanisms, leading to the formation of tumors and metastasis [4].

Traditional cancer treatments, including surgery, chemotherapy, and radiation therapy, have been the cornerstone of cancer management for decades. Surgery is often the primary choice for localized tumors, though it may not eliminate cancerous cells, leading to the risk of recurrence [5]. Chemotherapy and radiation therapy, classified as systemic treatments, target rapidly dividing cancer cells; however, they also affect healthy tissues, resulting in significant side effects such as immunosuppression and toxicity [6,7]. A major challenge with chemotherapy is the development of drug resistance, which reduces treatment efficacy over time [8].

In recent years, newer therapeutic modalities such as immunotherapy, hormone therapy, anti-angiogenic therapy, and stem cell therapy have emerged, offering more targeted approaches to cancer treatment [9]. Immunotherapy leverages the patient’s immune system to recognize and eliminate cancer cells, with advancements such as total exome sequencing paving the way for personalized medicine [10,11]. However, challenges such as treatment toxicity, tumor heterogeneity, and drug resistance still need to be addressed [12]. Ongoing clinical trials continue to explore novel strategies to enhance existing treatment outcomes [13].

2. Overview of Traditional Cancer Treatments

Exploring Conventional Cancer Therapies: Mechanisms and Limitations

Chemotherapy, radiation and surgery are the most common conventional cancer treatment methods and each of them has its own way of working and side effects [14]. The aim of chemotherapy is to kill the cancer cells which have the property of dividing fast. However, even these medications have drawbacks [see Table 1]. For example, paclitaxel is a chemotherapeutic agent with very poor water solubility that presents a few problems in transport and efficacy [14]. Radiation therapy uses high energy radiation to kill tumour cells, but it also has adverse effects on surrounding healthy tissues [14]. However, there is a problem of lack of specificity in chemotherapy and radiation therapy which deliver anti-cancer substances to specific sites. The concentrations are inadequate, and the toxins are toxic to non-cancerous cells [14]. This lack of specificity between cancer cells and normal cells is still a major problem in traditional cancer treatment methods.

Table 1. Common Radiation Regimens, Their Mechanism, Indications, and Side Effects.

Radiation Type	Mechanism of Action	Examples	Indications	Toxicities	Year	References
External Beam Radiation Therapy (EBRT)	Uses high-energy X-rays or protons to damage DNA and kill cancer cells	3D Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), Proton Beam Therapy	Breast, lung, prostate, brain, head and neck cancers	Skin irritation, Fatigue, Nausea, Fibrosis, Secondary malignancies	20th century – Present	[19]
Brachytherapy	Internal radiation therapy where a radioactive source is placed near the tumor	Low-dose rate (LDR), High-dose rate (HDR) brachytherapy	Prostate, cervical, breast, and endometrial cancers	Localized swelling, Tissue necrosis, Urinary dysfunction	20th century – Present	[20]
Stereotactic Body Radiation Therapy (SBRT)	Delivers high doses of radiation with pinpoint accuracy, sparing normal tissues	CyberKnife, Gamma Knife, LINAC-based SBRT	Brain, lung, liver, and spine cancers	Fatigue, Local tissue damage, Radiation necrosis	21st century	[21]

Table 1. Common Radiation Regimens, Their Mechanism, Indications, and Side Effects.

Radiation Type	Mechanism of Action	Examples	Indications	Toxicities	Year	References
External Beam Radiation Therapy (EBRT)	Uses high-energy X-rays or protons to damage DNA and kill cancer cells	3D Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), Proton Beam Therapy	Breast, lung, prostate, brain, head and neck cancers	Skin irritation, Fatigue, Nausea, Fibrosis, Secondary malignancies	20th century – Present	[19]
Brachytherapy	Internal radiation therapy where a radioactive source is placed near the tumor	Low-dose rate (LDR), High-dose rate (HDR) brachytherapy	Prostate, cervical, breast, and endometrial cancers	Localized swelling, Tissue necrosis, Urinary dysfunction	20th century – Present	[20]
Stereotactic Body Radiation Therapy (SBRT)	Delivers high doses of radiation with pinpoint accuracy, sparing normal tissues	CyberKnife, Gamma Knife, LINAC-based SBRT	Brain, lung, liver, and spine cancers	Fatigue, Local tissue damage, Radiation necrosis	21st century	[21]

Table 1b: Summary of radiation therapy modalities, their mechanisms, and associated side effects. This table provides insight into how external beam radiation therapy, brachytherapy, and stereotactic body radiation therapy target tumors while minimizing damage to surrounding healthy tissues.

Unravelling the Mechanisms of Traditional Cancer Treatments.

Formulations based on these cutting edge cancer therapies are less toxic yet without compromising on the effectiveness. The liposomal version of doxorubicin, Doxil, is a particularly good example since it improves the cardiotoxicity that is seen with the free doxorubicin [see Table 1] 21. When compared to the other available chemotherapeutic drugs, this is a rather large improvement. This formulation is important for cancer sufferers as the FDA authorized this formulation in the mid 1990s[Figure 1b]. As a result, Abraxane, which was a groundbreaking approach that demonstrated this improvement, involved the binding of the medication paclitaxel to albumin nanoparticles [Figure 1]. The side effects of the free form of paclitaxel are severe and well documented; however, the approximately 100 nm nanoparticle size of Abraxane improves solubility and reduces these effects [22]. The FDA approved Abraxane in 2005. These two examples of drug delivery with nanotechnology show that there is a continual effort to make conventional cancer treatments better by being more therapeutic with less systemic toxicity. The following are the differences between the new treatments of nanotechnology based treatments such as Doxil and Abraxane and the conventional cancer treatments. Nanotechnology based treatments such as Doxil and Abraxane have been developed to reduce some of the side effects that are associated with their classical counterparts, hence revealing the failures of the conventional cancer treatments. Most side effects of cancers and associated treatments are devastating, and conventional therapies for hematological malignancies are associated with several disadvantages that adversely affect the quality of life of the patients 23. For example, chemotherapy is a useful treatment for certain cancers but it also has many side effects, such as nausea, immunosuppression, which can lead to the development of various complications, including infection [24]. Furthermore, conventional radiotherapy for breast cancer has been for up to six weeks with one session per day, not only is it time consuming, but it requires a great deal of commitment and dedication from the patients which can often be not only stressful but also burdensome in the physical and psychological sense [25]. The only challenges are new cancer treatment and modalities that are much more targeted and less adverse to the patients compared to traditional modalities [26]. In fact, while traditional treatments have been the mainstay of cancer therapy, the increasing awareness of their limitations has spurred the search for new treatments that could improve therapeutic impact with reduced toxicity.

3. Targeted Therapy

Cancer treatment: Targeted therapy mechanisms. The impact of some of the severe side effects of classical treatments, which are improved by nanotechnology-based medicines such as Doxil and Abraxane, highlights the limitations of the traditional cancer therapies. Malignant blood diseases are usually treated with chemotherapy as the standard of care, and this form of treatment has several drawbacks that adversely affect the quality of life of the patients. For example, chemotherapy can stimulate a number of adverse effects including nausea, bone marrow suppression and thus immune suppression which is while it is useful in management of certain forms of cancer. This leaves patients prone to infections and other related complications [24]. For instance, conventional breast cancer radiation therapy has been given for a period of six weeks with a single session daily. This is not only time consuming but also requires a lot of patient care which is often a source of a lot of stress and burden in the physical and psychological form [25]. The challenges only call for new cancer treatment and modalities that can be much targeted and efficient with friendliness to the patients compared to traditional modalities [26]. However, targeted therapy can be used by itself or in combination with other treatments [30]. As doctors learn more about the specific mutations that are driving the cancer, they will be able to design ever more sophisticated treatments [27]. Targeted therapy is an effective and promising treatment option for some types of cancer as it is specific to the malignant cells and has fewer side effects than conventional chemotherapy. Varying Strategies in the Management of Cancer Therapies Targeted therapy is one of the four systematic cancer treatment approaches. Although the four types of cancer treatment are related, immune therapy is different from targeted therapy [33]. Targeted treatment drugs work on the abnormalities that are seen in cancer cells and not in normal cells. This paper aims to discuss the types of molecular targeted therapies, their action, effects, toxicity and the targets that are used in the management of cancer [34]. Among them, small molecule drugs and monoclonal antibodies are the most commonly used for targeted therapy in cancer [27,30]. Monoclonal antibodies are classified as targeted therapies despite the fact that they are classified as immunotherapies because they enhance the body’s immune system [27]. It is now feasible to attack cancer cells with monoclonal antibodies. In this case, small molecule drugs are designed to halt cell multiplication of tumor cells or even induce them to die. The molecules are small and thus can cross the cell membrane to reach intracellular targets [30]. Targeted therapies are now used clinically as first-line treatments for various human cancers and form the very foundation of precision medicine in cancer treatment [32].

Biological Markers in Targeted Cancer Therapy Across Various Cancer Types

It is important to find particular biological markers for different types of cancer in order to achieve the maximum possible effectiveness of cancer treatment. For instance, EGFR, ALK, ROS1, or BRAF are well-known molecular targets that can be employed for the management of metastatic NSCLC [31]. Many of the targeted medicines are designed to stop or halt signals that tell cancer cells to grow or to make them kill themselves [27]. For different kinds of cancer, targeted molecular treatment can also work on receptors, growth factors, cell surface antigens, or signal transduction pathways [30]. NSCLC is managed through targeted therapy of EGFR mutations, and the third-generation EGFR TKIs, such as osimertinib, have shown better clinical response [32]. Nevertheless, mutations like T790M and C797S are known to confer resistance to EGFR-TKIs [34]. The third generation of EGFR inhibitors, including EAI045, can block the signaling of T790M and C797S to overcome drug resistance [33]. Precision oncology needs tailored targeted alterations in advanced cancer to be recognized clinically for targeted therapy to work [34]. The expression of PD-L1 in tumors is a particular molecular marker that can be targeted by immunotherapy in some cancers [30]. Targeted molecular treatment works by halting the signaling that tells cancer cells to grow, disrupt the cell cycle or cause cancer cells to die [32].Top of For

a)

Immunotherapy

Revolutionizing Cancer Treatment: A Comprehensive Exploration of Immunotherapy and Its Contrasts with Traditional Approaches

By concentrating on the complex interactions between the patient’s immune system and tumour cells rather than the disease itself, immunotherapy marks a paradigm leap in the treatment of cancer [35,36]. Immunotherapy is distinguished by its specificity, focussing on tumour antigens that are either distinct or overexpressed by cancer cells, in contrast to conventional medicines that may impact both healthy and malignant cells [35]. This accuracy is partially attributable to developments like whole exome sequencing, which has transformed the detection of tumor-specific epitopes resulting from somatic mutations and made it possible to customise treatments based on each patient’s particular cancer profile [35]. Additionally, immunotherapies including vaccinations and adoptive T cell techniques aim to strengthen the patient’s immune system’s defences against these tumour antigens, providing a strategy that is not only more targeted but potentially more effective in harnessing the body’s natural defense mechanisms [35].

Types of Immunotherapy in Cancer Treatment

Immunotherapy, which goes beyond traditional treatments, has become a ground-breaking method of treating cancer and is completely changing the way that many types of cancer are managed.

• Chimeric antigen receptor (CAR) T-cell therapy

One of the most promising forms of immunotherapy is chimeric antigen receptor (CAR) T-cell treatment. The purpose of CAR T cells, also known as genetically engineered T cells, is to express CARs, which basically rewire immune cells to identify and attack cancer cells [35]. When these T cell receptors are designed to recognise and bind to specific antigens, antigens on the surface of tumour cells can be presented without the major histocompatibility complex (MHC) [35]. By allowing CAR T cells to target tumor-specific antigens, like IL-13Rα2, that the patient’s MHC does not display adequately, this is particularly helpful in preventing a common way that tumours elude the immune system [35]. Blood malignancies have demonstrated the efficacy of this treatment, with individuals having acute leukemia and lymphoma have responded well to treatment with CAR T cells [35]. The ongoing trials involving non-virus specific autologous T cells modified to express the HER2 CAR further demonstrate the adaptability of CAR T-cell therapy and raise the possibility of applying this treatment modality to other cancer types [35]. Activating the patient’s immune system in a targeted manner to eradicate tumor cells is the ultimate goal of immunotherapy, especially when CAR T-cell therapy is used [35].

b.

Antibody-Drug Conjugates (ADCs)

Combining strong cell-killing properties with accurate target recognition, antibody-drug conjugates (ADCs) are a novel approach to cancer treatment [Table 2]. Like precision-guided “biological missiles,” ADCs have the special capacity to precisely identify and eliminate cancer cells, maximising therapeutic effectiveness and reducing off-target side effects [37]. The process entails the monoclonal antibody of the ADC attaching itself to certain antigens on cancer cells, which causes endocytosis and lysosome and endosome maturation. Cell apoptosis or death is caused by the subsequent release of cytotoxic payloads that target DNA or microtubules and are aided by either chemical or enzyme-mediated processes [37].

Interestingly, a bystander impact may also be triggered by the discharged payload’s permeable or transmembrane character, increasing the overall effectiveness of ADC [38]. ADCs may also have an impact on the tumour microenvironment, which would increase their ability to kill. This novel approach has the potential to improve cancer treatment with less collateral damage and more accuracy [39].

ADCs in Clinical Development and Approved ADC Drugs

Antibody drug conjugates (ADCs) have become a potential class of medicines after decades of study and development [Table 2]. More than 100 ADCs were in clinical development worldwide as of December 2021, demonstrating the broad interest and promise in this area. Notably, 14 ADC medications have been approved for sale in various nations, which represents a major advancement in the treatment of cancer [40]. motetumomab pasudotox

Table 2 provides a summary of ADCs approved worldwide, with their indications, targets, years of approval, and marketing firms. In the year 2000, Pfizer approved gemtuzumab ozogamicin, which targets CD33, for treating acute myeloid leukaemia (AML). In the year 2011, Seagen launched benuximab vedotin, targeting CD30, for Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). Pfizer in 2017 approved itotumomab ozogamicin targeting the CD22 antibody for B-cell acute lymphoblastic leukemia B-ALL), and AstraZeneca allowed motetumomab pasudotox targeting the same CD22 target for hairy cell leukemia in the year 2018. For DLBCL, polatuzumab vedotin was sanctioned by Roche in the year 2019 targeting CD79b. Here are the various ADCs or antibody drug conjugates which marked new advances within targeted therapies related to various kinds of haematologic cancers.

C. Clinical trials have focused on oncolytic viruses, like Reolysin (pelareorep) and Talimogene laherparepvec (T-VEC), because of their capacity to specifically infect and destroy cancer cells. Numerous methods and strategies have been developed to increase their efficacy in cancer treatment [41]. In order to boost the viruses’ binding and entry into cancer cells, one technique is to alter the viral capsid to include certain ligands that target receptors that are overexpressed on tumour cells. Furthermore, oncolytic viruses that incorporate granulocyte-macrophage colony-stimulating factor (GM-CSF) might boost T-cell cytotoxic responses and antigen-presenting dendritic cells, hence increasing anti-tumor action [36].

Another tactic is to equip oncolytic viruses with cytokines such as interleukin-12 (IL-12), which have anti-angiogenic qualities and activate CD8 cytotoxic cells and natural killer cells. Furthermore, the immune response against cancer cells can be triggered by oncolytic viruses’ direct immunostimulatory effects on tumour cells. Maximising treatment outcomes depends on the use of the best oncolytic virus delivery methods, such as intratumoral and intravenous administration [36]. Developments in genetic engineering, delivery systems, and viral engineering have helped overcome obstacles such as tumour microenvironment barriers and immune reactions against oncolytic viruses.

Many viruses have shown promise as immunotherapies for a variety of cancers, including melanoma, brain malignancies, head and neck squamous cell carcinoma, lung and pleural cancer, and gastrointestinal cancers. Some of these viruses, such as adenoviruses, herpes viruses, measles virus, poxviruses, vesicular stomatitis virus, and New Castle disease virus, have shown encouraging clinical outcomes in ongoing clinical trials [42].

The effectiveness of oncolytic viruses has been investigated in clinical trials for a variety of cancers, such as melanoma, brain tumours, head and neck squamous cell carcinoma, lung and pleural cancer, and gastrointestinal cancers. Immunocheckpoint inhibitor (ICB) combination treatments, for example, have shown notable therapeutic advantages in the treatment of melanoma. It is necessary to clarify certain aspects of the combination treatments, such as if ipilimumab and nivolumab or other combinations with radiation or chemotherapy are used. However, there is hope for bettering the results of cancer treatment due to continuous research in this area.

Evolution of Immunotherapy: Milestones in Cancer Treatment

With the development of chemotherapy drugs, immunotherapy has also undergone much modification, especially with the discovery of enclitic biotherapy. It is a new therapeutic approach that triggers the immune system in a manner quite impossible with the conventional techniques through the induction of oncolysis by viruses. Replication-competent or replication-defective oncolytic viruses have been observed to trigger a cascade of immune responses starting with the overexpression of interferon (IFN) [35]. Overexpression of IFNs represents an important step that triggers the production of various cytokines acting as major regulators of T-cell trafficking. Such cytokines are important in directing T-cells to the tumour microenvironment, which ensures that the immune system specifically attacks the cancer cells [35]. Besides this, the structure of the tumor protected the endogenous tumor antigens from being presented. These antigens are released following the lytic viral infection. A plethora of antigens, in this case, can be recognized and targeted by the T-cells apart from the unmasking of the tumor to the immune system 35. Apart from antigen release, structural degradation of a tumor allows the infiltration of T-cells. The immune cells need to penetrate and destroy the cancer cells, which means tissue architecture needs to be disturbed, and extracellular matrix needs to be degraded [35]. Finally, type I IFNs are generated due to the interaction between viral infection and dendritic cells, which further amplifies the proinflammatory immune response and enhances the body’s ability to fight the tumor [35]. Thus, oncolytic virotherapy is a paradigm shift in cancer treatment from directly targeting the tumor cells to exploiting and amplifying the body’s immune response against cancer.

4. Limitations

The integration of immunotherapy with traditional cancer treatments holds great promise for improving patient outcomes and revolutionizing cancer care. Despite challenges such as immune resistance and adverse effects, ongoing research and technological advancements offer opportunities to overcome these barriers and optimize treatment strategies. By addressing these challenges and capitalizing on emerging innovations, we can usher in a new era of personalized and effective cancer therapy.

5. Conclusion

In summary, the present exhaustive systematic review has made it possible to reveal the present state, problems, and potential progress on the integration of immunotherapy with traditional cancer therapy. Immunotherapy is a breakthrough approach in the treatment of malignancies, having shown promising effects in various forms of cancers. The primary focus of our review was to provide an overall understanding of the synergies between immunotherapy and traditional treatments and improved outcomes, reduced resistance, and broader possibilities for therapy.

This has been highly promising, combining immunotherapy with the traditional treatments for cancer, such as surgery, chemotherapy, radiation therapy, and targeted therapies for various types of cancers. In most cases, the combination of these modalities resulted in higher response rates, longer survival, and lesser resistance compared with single approaches. Some specific chemotherapeutic agents therefore led to attributing these inhibitory effects on immunotherapy due to immunomodulating properties, the activation of antitumor immunity, and the facilitation of immune checkpoint inhibitors. However, other important factors involved optimal dosing, timing, and sequencing, whose exploration is much more needed.

Although the treatment results seem promising, there are still challenges such as identifying optimal combinations and managing potential toxicities. Ongoing research was encouraged in refining the treatment protocols, identification of predictive biomarkers, and unraveling difficulties in the tumor microenvironment. The review provided an underpinning need for a multidisciplinary approach, one that is cognizant of insights from oncology, immunology, pharmacology, and patient care, to fully appreciate interactions and effects of treatment.

The new technologies in spatial transcriptomics and single-cell sequencing had been recognized for their power to advance knowledge about the tumor microenvironment. These tools gave unparalleled insight into the interactions of cancer cells with the immune system and allowed for the development of precise and effective treatment approaches.

The integration of immunotherapy with other traditional cancer treatments does, however, hold great potential for revolutionizing cancer care and creating new avenues toward better treatment efficacy and improved patient outcomes. For the full therapeutic effect to be realized with this combined approach, continuous research, refinement of treatment strategies, and the integration of advanced technologies are imperative. This review provides significant input to the fast-moving era of cancer therapeutics, concerning the era of combined immunotherapy, where the multidisciplinary approaches and personalized treatment strategies play a very important role.

Looking ahead into the future trends wherein integration of immunotherapy with the traditional treatments will surely pave the way for effective cancer management along with the innovative research strategy. This combination represents a revolutionizing approach, wherein it has provided a hopeful trajectory in the improvement of survival rates and quality of life for the patients. Ongoing evolution by the paradigms that are continuously shaping the landscape toward precision and patient-centric approaches has created a transformative period in oncology.