Revolutionizing cancer treatment: the rise of personalized immunotherapies

Abstract

Interest in biological therapy for cancer has surged due to its precise targeting of cancer cells and minimized impact on surrounding healthy tissues. This review discusses various biological cancer therapies, highlighting advanced alternatives over conventional chemotherapy alone. It explores DNA and RNA-based vaccines, T-cell modifications, adoptive cell transfer, CAR T cell therapy, angiogenesis inhibitors, and the combination of immunotherapy with chemotherapy, offering a holistic view of the potential in cancer treatment. Additionally, it discusses the role of nanotechnology in increasing the efficacy of cancer-targeting drugs, as well as cytokine and immunoconjugate therapies for bolstering immune system effectiveness against neoplastic cells. The potential of gene potential for precise targeting of cancer-linked genes and the application of oncolytic viruses against virus-associated cancers are also discussed. The review identifies significant advancements in the targeted treatment of cancer by biological methods. It acknowledges the challenges, including drug resistance and the need for high specificity in certain therapies, while also highlighting the effectiveness of cancer vaccines, modified T-cells, and oncolytic viruses. Biological therapies are a promising frontier in cancer treatment, offering the potential for more personalized and effective therapeutic strategies. Despite existing challenges, ongoing research and clinical trials are fundamental for overcoming current limitations and enhancing the efficacy of biological therapies in cancer care.

Introduction

Cancer is one of the most complex and challenging disease that has long been the focus of intense clinical research and investigations, being a leading cause of mortality worldwide [1]. As the conventional cancer treatment options, chemotherapeutics have certain limitations that substantially effects the effectiveness of treatment significantly interfering with the patient’s quality of life which highlights the need of new treatment options [2, 3]. To date chemotherapy is still the most opted treatment option for cancer treatment despite its limitations of non-specificity, drug resistance, and variability in effectiveness which further highlights the importance of development of more targeted and combination approaches as a therapeutics for cancer [3, 4].. Recent advancements in the biological therapies, immunotherapy, and gene therapy are reshaping the landscape of cancer treatment, opening the new horizons of hope for improved patient outcomes with better quality of life, and good survival rates. Moreover, these innovative options leverage enhanced understanding of the cancer biology and its microenviroment allowing the development of more personalized treatment strategies that aim to address the unique molecular characteristic of individual tumors [4, 5]. The biological cancer therapy includes compounds that are processed in the laboratory or are present naturally in the body. These methods either directly kill the cancer cells or they direct and enhance the activity of the immune system to attack cancer cells. The research and advancements in the development of biological cancer therapies have been proceeding promptly because of their ability to specifically target the problem [6, 7]. Next-generation sequencing (NGS) detection methods are used in targeted therapies to help identify the rare mutations associated with cancer cells and enable personalized treatment for the patient [8]. The biological cancer therapies have been observed to induce genetic changes in the tumor suppressor gene and oncogenes which plays important role in tumor progression.Different moleculeshave been developed as a targeted therapy to treat specific cancer. To name a few Vemurafenib is used as an inhibitor of BRAF serine/threonine kinase in melanoma patients;, Osimertinib, a FDA and EMA (2017) approved drug for treatment non-small-cell lung cancer (NSCLC) associated to a EGFR T790M mutation; Imatinib, a BCR-ABL which is tyrosine kinase inhibitorhelps in treating chronic myeloid leukemia by inhibiting the BCR-ABL activity, which halts the proliferation ok leukemic cells eventually improved survival rates and clinical remission of CML patients [9–12]. In the development of cancer, different factors in its microenvironment play important roles including proliferation, drug resistance, adhesion, and migration of the cancer cells. The information on these factors will help in studying cancer and provide possible solution for this problem. The objective of this paper is to examine the recent advancements in biologics therapy and to explore their potential for cancer therapy in a more effective manner as compared to conventional therapy alone. By understanding the underlying biology of cancer, and employing these innovative approaches for more targeted personalized and efficacious treatment options to reduce cancer burden.

Review methodology

For collecting the relevant material for this review search engines such as Google Scholar, PubMed and Science Direct were used. The data was collected using the following keywords such as “Cancer”, “Biological therapy”, “Cancer Vaccines”, “Angiogenesis inhibitors”, “Adoptive cell transfer”, “Monoclonal antibodies”, “Immune checkpoint modulators”, “Biochemotherapy”, “Chimeric antigen receptor (CAR) T-cell therapy”, “Cytokine therapy”, “Targeted drug therapy”, “Bacillus Calmette-Guerin therapy”, “Gene therapy”, “Immunoconjugates” and “Oncolytic virus therapy”. This paper also covers the ongoing clinical trials for biologics therapy and their outcomes.. The data that were not in English and were not published in any reliable journal were also excluded from the study.

Types of biological therapy

There are different types of biological therapies for cancer and they include: cancer vaccines, angiogenesis inhibitors, adoptive cell transfer, monoclonal antibodies, immune checkpoint modulators, targeted drug therapy, chimeric antigen receptor (CAR) T-cell therapy, targeted drug therapy and chemotherapy, cytokine therapy, Bacillus Calmette-Guerin therapy, gene therapy, immunoconjugates and oncolytic virus therapy.

Cancer vaccines

The employability of cancer vaccines has been explored for the prevention as well as for the treatment of cancer, which act by leveraging the body’s immune system to combat tumor growth. [13]. Cancer vaccine can work by stimulating the immune system to recognize and attack cancer cells by the introduction of specific antigens associated with tumors, or vaccines against specific viral infections like HPV and HBV which can lead to cervical and liver cancer, helps as a prevention [14, 15]. To develop a cancer vaccine, it is important to recognize the neo-epitope or antigen targets on the cancer cells. The immune system will be unable to recognize the proteins present on the cancer cells since CD4 + and CD8 + T cells cannot identify these proteins on cancer cells as foreign particles [16]. Anticancer vaccines introduce cancer-specific antigens into the body. The vaccine components are taken up by antigen-presenting cells (APCs), such as dendritic cells, which process the antigens and present them on their surface [17]. The antigens presented are identified by t-Cell through their receptors (TCRs). This recognition, facilitates the activation of T-cells, particularly in conjugation with co-stimulatory signals provided by antigen-presenting cells (APCs) CD8 + T cells can directly target and kill cancer cells presenting the same antigens, while CD4 + T cells provide help by secreting cytokines that enhance the immune response [18]. A successful anticancer vaccine not only triggers an immediate immune response against cancer cells but also establishes a population of memory T cells. These cells persist for longer time and can quickly establish an immune response if the cancer antigens are encountered again, providing ongoing surveillance against cancer recurrence [18].

Neoantigens, which are unique protein fragments resulting from tumor-specific mutations, play a fundamental role in cancer vaccines by enabling highly personalized and targeted immune responses against cancer cells [19]. Targeting these neoantigens allows for the development of highly personalized cancer vaccines, which can enhance the immune response specifically against a patient’s tumor:

• i.Personalization: neoantigen-based vaccines offer a tailored approach by focusing on the unique mutations present in an individual’s tumor, leading to a more targeted immune response [19].
• ii.Efficacy and safety: these vaccines have the potential to elicit robust immune responses while minimizing off-target effects, reducing the risk of adverse effects compared to traditional therapies [19].
• iii.Challenges in identification: the identification of suitable neoantigens is complex, requiring advanced bioinformatics tools and genomic analyses to predict which neoantigens will be most effective in stimulating the immune system [20].
• iv.Clinical trials and outcomes: ongoing clinical trials have shown promising early results, with neoantigen-based vaccines leading to significant tumor reduction in some cancers. However, larger-scale trials are needed to validate these findings [21].
• v.Integration with other treatments: neoantigen vaccines can be combined with other treatments, such as immune checkpoint inhibitors, to enhance their efficacy, paving the way for more comprehensive cancer treatment strategies [22].

The primary result of an effective anticancer vaccine is the activation of an immune response specifically targeted at cancer cells [23]. This can cause a reduction of tumor size, slowing of tumor growth, and in some cases, complete eradication of the tumor [24]. In clinical settings, successful anticancer vaccines have been associated with improved survival rates for patients and, in some cases, a reduced risk of cancer recurrence. This is particularly important in diseases like melanoma, where vaccines targeting antigens like gp100 have shown promising results [24]. Anticancer vaccines are often used in combination with other therapies, such as chemotherapy, radiation therapy, or immune checkpoint inhibitors and such a multimodal approach can increase the overall effectiveness of treatment by targeting cancer through different mechanisms [25] (Fig. 1).

Fig. 1.

Mechanisms of action of anticancer vaccines and immune activation. The vaccine, containing components such as dendritic cells, cancer cells, synthetic peptides, and nucleic acids (DNA and RNA), is administered to the patient. Once injected, these components are processed in the lymph nodes, causing the activation of CD4 + T cells and CD8 + T cells. The activated CD4 + T cells assist in further activating CD8 + T cells, which in turn release cytokines that have an important role in increasing the immune system's response to cancer cells. As a result, the immune cells infiltrate the cancer tissue causing the death of cancer cells. Symbol: ↑increase

There are different types of cancer vaccines for cancer treatment and they include: tumor or dendritic cell-based cellular vaccines, long synthetic peptide (SLP) vaccines, and DNA or RNA-based vaccines [26, 27]. The nucleic acid-based vaccines are made up of DNA and RNA molecules. The RNA-based cancer vaccines contain antigens coding for mRNA that have been translated from the normal cells and this helps with tailored neoantigen vaccination. [28]. The most important role of the proteins coded by mRNA to become antigenic occurs because of the proper folding of protein after different modifications including acetylation, glycosylation, phosphorylation, or methylation [29]. The antigen-specific immune response can also be mediated by the help of DNA vaccines that have bacteria as a source and contain the closed circular plasmid DNA which is converted to mRNAs and then translated to the desired protein. These vaccines are involved in initiating the adaptive immune response just like RNA-based vaccines. The advancement in the development of cancer vaccines has positioned mRNA as the promising vaccination for cancer treatment [30]. When compared to RNA vaccination, DNA-based cancer vaccines are more stable but their delivery is difficult because they require proper localization in the nucleus [31]. The clinical trials conducted with nucleic acid-based (RNA and DNA) vaccines are presented in Table 1.

Table 1.

The clinical trials are being conducted on the nucleic acid-based vaccines used for cancer

Vaccines/ Drugs	Investigation Plan	Clinical Setting Lines of therapy	Primary Endpoint	Phases of Clinical Trial	Clinical Trials Status	Clinical Trial Identifier Code
PDC*lung01, Keytruda Injectable Product, Alimta	64 participants, Non-Randomized, Sequential Assignment, Open label	Wash out of 4 weeks since last cycle of chemotherapy	DLT	1/2	Recruiting	NCT03970746
Vlagenpumatucel-L, Nivolumab, Pembrolizumab, Pemetrexed	121 participants, Non-Randomized, Parallel Assignment, Open label	Second or later	TEAEs, ORR, PFS	1/2	Active, not recruiting	NCT02439450
K27M Peptide, Nivolumab	49 participants, Non-Randomized, Parallel Assignment, Open label	Second line	K27M peptide, Nivolumab	1/2	Recruiting	NCT02960230
GVAX, Busulfan, Fludarabine, Tacrolimus, Methotrexate	123 Participants, Randomized, Parallel Assignment, Triple (Participant, Care Provider, Investigator)	First line	18/month PFS	2	Active, not recruiting	NCT01773395

DLT Dose-limiting toxicity, GVAX Granulocyte–macrophage colony-stimulating facto secreting allogeneic pancreatic tumor vaccine, NCT National clinical trial (identifier code), ORR Overall response rate, PDC*lung01 Personalized dendritic cell lung cancer vaccine 01 (assumed, as specific meaning not provided), PFS Progression-free survival, TEAEs Treatment-emergent adverse events

Adoptive cell transfer

Adoptive cell transfer (ACT) is a type of cancer therapy that genetically modifies and destroys the cancer cells after recognizing them by using T cells (Fig. 2). The important role of ACT is to modify the natural immune defense thus playing a significant role in cancer treatment [32]. The ACT was developed in the last 30 years and it seems that it can help in the treatment of cancer by using two of its essential components T-cell Receptor-T (TCR-T) therapy and chimeric antigen-receptor (CAR) T-cell therapy [33]. Both of these types of ACT have some limitations. Therefore, there is a need to evaluate and implement tumor-specific antigens for adequate cancer treatment [34].

Fig. 2.

Adoptive Cell Transfer Therapy (ACT) in cancer treatment. The process begins with the collection of peripheral blood from an oncologic patient, followed by the isolation of T cells. Simultaneously, tumor-infiltrating lymphocytes are also extracted directly from the patient’s tumor. Both undergo a phase of activation and selection, where T cells are stimulated to enhance their cancer-suppressing abilities. Subsequently, these T cells are genetically modified to express specific tumor-targeting receptors, either TCR (T cell receptors) or CAR (chimeric antigen receptors). The engineered T cells are then expanded in the laboratory to create a large quantity of targeted anti-cancer cells. The final step involves re-infusing these modified T cells back into the same patient, where they are expected to find and destroy cancer cells, offering personalized and targeted cancer therapy

The impact of tumor microenvironment on ACT efficacy

• i.Immune suppression: the tumor microenvironment (TME) is characterized by the presence of immune-suppressive factors, such as regulatory T cells, myeloid-derived suppressor cells, and cytokines [35]. These elements can inhibit the function of transferred T cells, limiting the efficacy of ACT. Overcoming this suppression remains one of the key challenges in making ACT more effective [36].
• ii.T cell exhaustion: within the TME, transferred T cells can become exhausted due to persistent antigen exposure and inhibitory signals. Strategies to overcome T cell exhaustion, such as combining ACT with immune checkpoint inhibitors or engineering T cells with enhanced resistance to exhaustion, are important for improving patient outcomes [37].
• iii.Microenvironmental modulation: modifying the TME can significantly enhance ACT effectiveness. Approaches such as depleting suppressive cells, altering cytokine profiles, and using VEGF/VEGFR inhibitors to prevent tumor angiogenesis are currently under investigation and show promise in augmenting the success of ACT in clinical settings [35].
• iv.Biomarkers for success: identifying reliable biomarkers that predict ACT success is vital for improving patient selection. By tailoring treatments based on tumor-specific biomarkers, clinicians can optimize ACT strategies for each patient, increasing the likelihood of positive outcomes [38].
• v.Personalization of therapy: the heterogeneity of tumors and the complexity of their microenvironments necessitate a personalized approach to ACT. Individual tumor characteristics, such as the specific antigen profile and the nature of the TME, must be considered when designing ACT therapies. Personalized treatments that adapt to these factors are essential for achieving the best therapeutic results [39].

A recent study conducted on metastatic melanoma patients and animal models has reported that immunotherapies based on ACT have shown a reduction of tumors. Nevertheless, the anti-tumor immune response can be stopped by tumor angiogenesis by obstructing the tumor-infiltrating lymphocytes (TIL). The the role of ACT in cancer model was studied after suppressing the vascular endothelial growth factor/receptor (VEGF/VEGFR-2) signaling pathway [36]. A phase II clinical trial (NCT01174121) is currently evaluating the safety and efficacy of TIL on multiple tumors of the breast, digestive tract, endometrial, ovarian and urothelial tumors. Advancements in these clinical trials may provide substantial insights into the ability of TIL to be used as a cancer therapy.

Chimeric antigen receptor (CAR) T-cell therapy

Chimeric antigen receptor T-cell therapy is considered as a revolutionary technique when compared with the other two types because it helps treating and eliminate the cancer completely [40–42]. Chimeric antigen receptors (CAR) can activate different processes controlled by T-lymphocytes that are engineered with CAR after their signaling domain is activated by outside signals. CAR receptors have monoclonal antibodies and are also called synthetic receptors. Viral vectors like retroviruses or lentiviruses are used to trigger the chimeric antigen receptors on the engineered T lymphocytes and this is achieved when these viral vectors transfer the protein-coding sequence. Such engineered CAR T cells have similar roles to T cells including the expression of long-term protection of patients and initiating the immune response to cancer cells [43–45].

The study conducted on hematological cancers treated with CAR T cell therapy showed positive results [46]. The chimeric antigen receptors consist of different components which include the CD3ζ receptor’s membrane fragment, the costimulatory component of the T cell receptor and the Fv domain fragment (single-chain) for the tumor antigen [47]. These components are present in the membrane of CAR T cells. There are many costimulatory molecules including OX40, CD28, ICOS, 2B4 (CD244), NKG2D, 4-1BB and DAP10. The chimeric receptor does not need major histocompatibility complex (MHC) I to recognize the tumor antigen [48]. The particular tumor microenvironment has been a reason for the restricted access of tumor cells for CAR T cell therapy. The activation of CAR T cells is required to overcome this problem which causes the formation and secretion of heparanase (HPSE) but CAR T cells are unable to destroy the extracellular matrix in a tumor because they cannot produce HPSE [49]. Antitumor activity can be achieved by CAR T cells if they are modified in such a way that they start to produce HPSE allowing these cells to penetrate the extracellular matrix of the neoplasm [50]. Recent clinical trials, (NCT02715362, NCT03198546, and NCT02905188) showed CAR-T cells specifically targeting glypican-3 (GPC-3) to be effective against GPC3-positive hepatocellular carcinoma (HCC) [51].

Angiogenesis inhibitors

For the past 50 years studies on angiogenesis and tumors have been conducted. Initially, the survival multiplication and growth of the tumor cells were studied but now this concept has expanded to different diseases like rheumatoid arthritis (RA), diabetic retinopathy, and cardiovascular diseases [52]. The anti-tumor therapy can be performed by developing inhibitors of angiogenesis. Therefore, anti-angiogenic drugs that reduce the supply of blood to the tumor tissues might be used. The vascular endothelial growth factor and receptor (VEGF/VEGFR) signaling pathway is believed to be more significant in the angiogenesis of cancer cells. So, studies were mostly conducted to develop anti-angiogenic drugs targeting this pathway [53]. Different drugs that have been approved for anti-angiogenic therapy include monoclonal antibodies, oligonucleotide aptamers, recombinant fusion proteins, mTOR inhibitors, immunomodulatory agents, and tyrosine kinase inhibitors and are presented in Table 2.

Table 2.

Angiogenesis inhibitors approved by FDA for clinical cancer therapy

Drugs	Targets	Adverse effects
Monoclonal antibodies
Bevacizumab	VEGF-A	Dry skin, headache, back pain, taste alteration, arterial or venous, exfoliative dermatitis gastrointestinal proliferation, hemorrhage, hypertension, lacrimation disorder, poor wound healing, rhinitis, proteinuria, and thrombosis
Ranibizumab	VEGF-A	eye infection, eye pain, increased intraocular pressure, Endophthalmitis, floaters, rhegmatogenous retinal detachment, conjunctival hemorrhage, and retinal hemorrhage
Ramucirumab	VEGFR-2	Abdominal pain, constipation, cough, diarrhea, dyspnea, nausea, and vomiting Anorexia, arthralgia, epistaxis, fatigue, headache, hypertension, Leucopenia, thrombocytopenia, neutropenia, proteinuria, Peripheral edema, upper respiratory tract infection
Olaratumab	PDGFR-α	Appetite, abdominal pain, diarrhea, nausea and vomiting Decreased fatigue, headache, neuropathy, musculoskeletal pain, mucositis, and alopecia
Bevacizumab-awwb	VEGF	Altered taste, dry skin, headache, arterial and venous thromboembolic events, bleeding, epistaxis, exfoliative dermatitis, Hypertension, infusion-related reactions, lacrimation disorders, ovarian failure, perforation or fistula, post-reversible encephalopathy syndrome, proteinuria and rhinitis
Oligonucleotide aptamers
Pegaptanib	VEGF-A165	Retinal-detachment and endophthalmitis
Recombinant fusion proteins
Aflibercept	VEGF-A, VEGF-B, PIGF	Decreased vision, floaters, eye pain, Cataracts, vitreous detachment, increased intraocular pressure, and conjunctival hemorrhage,
Ziv-Aflibercept	VEGF-A, VEGF-B, PIGF	Abdominal pain, epigastric pain, diarrhea, dyspnea, decreased appetite, gastrointestinal perforation, weight loss bleeding, decreased ejection fraction, Fatigue, headache, impaired wound healing, infection, leukopenia, nephrotic syndrome, neutropenia, osteonecrosis of the lower jaw, proteinuria, stomatitis, thrombocytopenia, heart failure, and hypertension
mTOR inhibitors
Temsirolimus	mTOR	Nausea, interstitial pneumonia, asthenia, edema, elevated aspartate aminotransferases, hyperlipidemia, hypersensitivity, intestinal perforation, lymphopenia, thrombocytopenia mucositis, acute renal failure,
Everolimus	mTOR	Canker sores, tongue ulcers, paronychia, rash, swollen and painful gums, tiredness, and increased heart rate,
Immunomodulatory agents
Thalidomide	VEGF-A, TNF, NF-kB	Abdominal pain, nausea, constipation, dizziness, drowsiness, facial puffiness, dry oral mucosa, rash, teratogenic, and tiredness
Lenalidomide	VEGF-A, TNF, NF-kB	Diarrhea, fatigue, headache, loss of appetite, low back pain, anemia, neo-malignant neoplasma, neutropenia, rash, renal complications, thrombocytopenia, and thrombotic complications
Tyrosine kinase inhibitors
Sorafenib	VEGFR-1/-2/-3, c-Kit, Fit-3, PDGFR-β, Raf, Ret	Abdominal pain, decreased appetite, diarrhea, fatigue, nausea, rash weight loss, alopecia, hand-foot skin reaction, and hypertension,
Sunitinib	VEGFR-1/-2/-3, Fit-3, c-Kit, Ret, PDGFR-α/-β, CSF-1R	Abdominal pain, asthenia, fatigue, diarrhea, dysgeusia, dyspepsia, hypertension, anorexia, mucositis, nausea, thrombocytopenia skin discoloration, and stomatitis
Pazopanib	VEGFR-1/-2/-3, c-Kit, PDGFR-α/-β	Anorexia, diarrhea, fatigue, hair color changes, nausea, vomiting, and weight loss
Vandetanib	VEGFR-2, VEGFR-3, EGFR, Ret	QTc prolongation, diarrhea, headache, rash, hypertension, and nausea
Regorafenib	VEGFR-1/-2/-3, c-Kit, PDGFR-β, Ret, Raf-1, bRaf, FGFR-1, Tie-2	Anorexia, diarrhea, fatigue, hand-foot, skin reaction, oral mucositis and hypertension
Axitinib	VEGFR-1/-2/-3, c-Kit, PDGFR-α, PDGFR-β	Decreased appetite, dysphonia, fatigue, diarrhea, asthenia, hypertension, nausea, vomiting, decreased weight, constipation, and hand-foot syndrome
Ponatinib	VEGFRs, PDGFR, EPHs, FGFRs, ABL, Src, Ret, LYN, LCK, c-Kit, HCK, FYN, FRK, c-FMS, FGR, BLK	Abdominal pain, fatigue, dermatitis, dry skin, elevated lipase, nausea, rash, arthralgia, and thrombocytopenia
Cabozantinib	VEGFR-2, c-Met, c-Kit, Ret, Fit-3, Tie-2, AXL, RON	Asthenia, constipation, decreased appetite, decreased weight, diarrhea, dysgeusia, nausea, oral pain, fatigue, hair color changes, palmar-plantar, hypertension, erythrodysesthesia syndrome, and stomatitis
Apatinib	VEGFR-2, Src, c-Kit	Fatigue, gastrointestinal bleeding, granulocytopenia, hoarseness, hypertension, proteinuria, leukopenia, thrombocytopenia, and hand-foot syndrome
Nintedanib	VEGFRs, FGFRs, PDGFR, Fit-3, LCK, LYN, Src	Bleeding, decreased appetite, diarrhea, nausea, vomiting, electrolyte imbalance, mucositis, neutropenia, rash and peripheral neuropathy
Lenvatinib	VEGFRs, PDGFR, Ret, c-Kit, FGFRs	Abdominal pain, decreased appetite, decreased weight, arthralgia, diarrhea, nausea, vomiting fatigue, headache, dysphonia, hypertension, myalgia, proteinuria, and stomatitis

ABL Abelson murine leukemia viral oncogene homolog, c-Kit Tyrosine-protein kinase Kit, c-Met Mesenchymal-epithelial transition factor, CSF-1R Colony-stimulating factor 1 receptor, EGFR Epidermal growth factor receptor, FGFRs Fibroblast growth factor receptors, Flt-3 Fms-like tyrosine kinase 3, LCK Lymphocyte-specific protein tyrosine kinase, LYN Tyrosine-protein kinase Lyn, mTOR Mammalian target of rapamycin, NF-kB Nuclear factor kappa-light-chain-enhancer of activated B cells, PDGFR Platelet-derived growth factor receptors, PlGF Placental growth factor, Raf Rapidly accelerated fibrosarcoma, Ret Rearranged during transfection, Src Proto-oncogene tyrosine-protein kinase Src, Tie-2 Tyrosine kinase with immunoglobulin-like and EGF-like domains 2, TNF Tumor necrosis factor, VEGFRs Vascular endothelial growth factor receptors, VEGF-A Vascular endothelial growth factor A

Monoclonal antibodies

The monoclonal antibodies (mAb) bind to the specific type of antigen epitope and these antibodies are produced from special B cells. In 1973, Schwaber described a method to produce mAb by using human-mouse hybrid cells. For the large-scale production of mAb, Kӧhler and Milstein used human-derived hybridomas [54, 55]. The next step was to study the role of mAb as an option for cancer therapy. A study was conducted on the lymphoma patients in 1980 which was the first clinical trial on humans. It showed that mAb might be the best treatment for this cancer. Another study on mice showed the role of anti-melanoma mAb in decreasing the growth of human melanomas [56, 57].

• i. Specificity and mechanism of action

• Monoclonal antibodies are highly specific to cancer cells, targeting unique antigens expressed on their surface [58]. This specificity allows for targeted therapy, minimizing damage to healthy tissues. mAb exert their effects through various mechanisms, including direct inhibition of tumor cell growth by blocking receptor-ligand interactions, recruitment of immune effector cells via antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), and the delivery of cytotoxic agents through antibody–drug conjugates (ADCs). These mechanisms enhance the therapeutic potential of mAb in cancer treatment [58].

• ii. Combination therapies

• Monoclonal antibodies are increasingly used in combination with other cancer therapies, such as chemotherapy, radiation, and immune checkpoint inhibitors [59]. These combination approaches can enhance treatment efficacy by attacking cancer cells from multiple angles. For instance, combining mAb with checkpoint inhibitors can help overcome immune resistance, while pairing them with chemotherapy can increase the cancer cells' susceptibility to immune attack, leading to improved patient outcomes [59].

• iii. Resistance mechanisms

• Despite their effectiveness, tumor cells can develop resistance to mAb. Resistance mechanisms include antigen loss, where tumor cells downregulate or mutate the targeted antigen, and the upregulation of alternative signaling pathways that bypass the blocked receptor [60]. Understanding these resistance mechanisms is important for developing strategies to overcome them, such as using bispecific antibodies or combining mAb with other therapies to target multiple pathways simultaneously.

• iv. Personalized medicine.

• The success of monoclonal antibody therapies is often dependent on the identification of specific biomarkers that predict a patient’s response to treatment. Genetic profiling of tumors is essential for guiding the selection of appropriate mAb therapies, ensuring a personalized approach to treatment [61]. As precision medicine continues to advance, integrating biomarker identification into clinical practice will enable more targeted and effective use of mAb in oncology.

• v. Adverse effects and management

• While monoclonal antibodies are generally well-tolerated, they can still lead to adverse effects, such as infusion-related reactions, cytokine release syndrome (CRS), and immune-related complications [62]. Proper management of these side effects is crucial to optimizing patient care and maintaining treatment adherence. Pre-medications, careful monitoring during infusions, and prompt intervention for any adverse reactions can help mitigate these risks and improve patient outcomes [63]

mAb have been important drugs to treat cancer and different modifications were done on mAb by using antibody engineering. Antibodies can either directly attack the cancer cells or they can just stimulate the host immune system to generate a long-lasting immune response and kill the cancer cells. The strong anti-tumor response and relatively rare adverse effects of the mAb have made them the better choice to treat cancer than other therapies like chemotherapy [64]. FDA-approved mAb for treatment of cancer are presented in Table 2.

Immune checkpoint modulators

The immune checkpoint modulators are defined as the molecules that play a protective role in the immunity, they have significantly transformed cancer treatment, leading to improved patient outcomes for various malignancies[65]. Many different immune checkpoint inhibitors have been studied as potential anti-cancer drugs for the past few decades and including BTLA, CTLA-4 [66], TIM3 [67], PD-1 [68], TIGIT, VISTA [69] and LAG3 [70, 71]. To perform their inhibitory role these molecules stimulate the immune receptors that have been produced, and for this process, they use two different mono-tyrosine signaling motifs include the immunoreceptor tyrosine-based switch motif (ITSM) and immunoreceptor tyrosine-based inhibitory motif (ITIM). The ligand-receptor activity can be stopped by blocking the antibodies. nti-PD-1/PD-L1 therapy is considered the most effective immune checkpoint modulator for treating different types of cancers such as lung, liver, blood, kidney, bladder and skin cancers [72]. However, this therapy has shown no effect on colorectal cancer that has the integrity of microsatellites [73].

Tumor microenvironment have increased expression of immune checkpoint on the cell surface, which is considered an important hallmark. The immune checkpoint modulators are membrane proteins and are initially localized in the endoplasmic reticulum (ER). Afterwards, they pass through the protein trafficking system, including the Golgi apparatus and vesicles and they move to the cell surface to perform their inhibitory role. In this whole process, glycosylation plays an important role in transporting the efficient immune checkpoint modulators to the cell surface [74, 75]. The regulation of these molecules and their function on the surface of the cells can be maintained after their recycling and internalization [76, 77]. CA-170 has been one of the first agent in clinical trials as an antagonist of PD-L1, PD-L2, and VISTA. The clinical trials in phase 1 (NCT02812875), yielded pharmacological safety and effectiveness.

This type of biological cancer therapy has shown a persistent response and can be remembered by the immune system thus being more effective than other targeted chemotherapies. Despite the advantages, different drawbacks have been associated with immune checkpoint modulators which decrease the clinical response rate of such therapy from 10 to 30 percent for most cancers. Despite limitations, several novel immune checkpoint molecules have showed promising results in pre-clinical and clinical trials [72, 78].

Biochemotherapy

Among the different therapies for cancer treatment cytotoxic chemotherapy is the oldest one [79]. It includes the drugs that are specifically made to kill the rapidly dividing cancer cells, but this technique has several adverse effects since it can kill the normal healthy cells as well. Another approach that can be used as an alternative is immunotherapy, which enhances the function of the immune system in order to treat cancer. Another improvement for cancer treatment can be made if both the above techniques are combined and this treatment strategy is named biochemotherapy [80].Interferon and interleukin 2 (IL-2) immunotherapy are components of biochemotherapy. The clinical trials (NCT04405349, NCT04410445, NCT04526730) have been done on the patients with metastatic melanoma and it was shown that the patients have an increased response rate when they were treated with combined immunotherapy and the chemotherapy [81].

Targeted drug therapy

Cancer is characterized by uncontrolled growth that will lead to the increased progression of the disease [82]. Chemotherapy for the treatment of cancer has a lot of different adverse effects since it is non-specific, and targets cancer cells as well ashealthy cells and tissues to a certain extent [83]. The disadvantages of conventional cytotoxic anticancer drugs are therefore; non-specific biodistribution, inadequate distribution of drug at tumors or cancer cells, poor aqueous solubility, development of multiple drug resistance, and severe toxicity to normal healthy cells [84, 85].

In recent years, he substances that are used for drug delivery are modified by nanotechnology which alters the pharmacokinetics of the drug [86]. When the nanomedicines are compared with the conventional chemotherapy such modified drugs have shown different biodistribution and an increased plasma half-life. This occurs because of the modifications of the drugs by dissolving them in hydrophilic and hydrophobic compartments causing their reduced metabolism and by increasing their solubility. One of the phenomena associated with the effect of nanomedicines on the tumor was named enhanced permeability and retention (EPR) effect and it explains the accumulation of nanomedicines at the site of tumor. Nanomedicines can easily cross the endothelial layer of the vessels in the tumor microenvironment having the range of 300 to 4700 nm in diameter. This enables nanomedicines to reach the tumor’s interstitial fluid site easily when compared to the other normal tissues that have the tight bindings and functional lymphatic drainage [87–90].

Cytokine therapy

Cytokines have a molecular weight of 30 kilo Daltons and are polypeptides or glycoproteins. They play different roles in different processes in the cells such as; differentiation, inflammatory or anti-inflammatory signals, and also control of cell growth. Cytokines have a short half-life when they are in the circulation as a response to a stimulus. They bind to the receptors on the membrane of the target cells. This binding further causes different intracellular processes and changes in the transcription of the genes. It is also involved in the modification of other cell functions such as differentiation and proliferation [91]. Cytokines are the components of the natural and acquired immune system and they act as messengers for the immune cells to communicate in the autocrine and paracrine manner to the nearest sites. This activity of cytokines enables the immune system to identify cancer cells and to kill them. Therefore, cytokines therapy might be an interesting approach to treat cancer. The study on the mouse tumor model has shown the importance of different cytokines like granulocyte–macrophage-colony-stimulating factor (GM-CSF), interferon alpha (IFN-α), interleukin (IL)-12, IL-2, IL-21 and IL-15 [92–99]. In 1986, the first cytokine that was used for treating human hairy cell leukemia (HCL) was IFN-alpha. In 1992 after going through different treatment protocols for metastatic renal cell carcinoma (mRCC) treatment, high dose of IL-2 (HDIL-2) was used. HDIL-2 was also used to treat metastatic melanoma (MM) in 1998 [100]. Cytokines have anticancer effect by immune cell activation or by directly inducing apoptosis or anti-proliferative action against the tumor cell growth [91]. In cancer immunotherapy, cytokines have played an important role since this approach was the first to create a balance between anti-tumor immune response and cancer. Studies have reported that the high dose of IFN-α and IL-2 although having high toxicity and low response rate, when used with immune checkpoint inhibitors and targeted therapy clinically have achieved favorable results [101, 102].

Bacillus Calmette-Guerin therapy

In 1891, Dr. William B. Coley used microbial-derived products for cancer treatment. Patients were treated with live Streptococcus pyogenes by directly injecting these immune-stimulating agents into the tumor. Also, a mixture of Serratia marcescens and S.pyogenes was used [103, 104]. Similarly, the mice were infected with the Bacillus Calmette-Guerin (BCG) intravenously at the Sloan-Kettering Institute in New York by Dr Lloyd Old which has resulted in controlling the tumors that were transplanted to them [105]. Then BCG was used as a therapy for different types of cancers such as melanoma and acute lymphoblastic leukemia [106, 107]. In 1976, a successful study was done in which patients with bladder cancer were treated with BCG, and positive results were obtained [108]. The live-attenuated strain of Mycobacterium bovis was used to make the BCG vaccine but this strain was initially made from the most virulent one that was reported by Guerin and Calmette in 1908 at the Paster Institute [109]. The effects of BCG against cancer can be achieved by activation of an inflammatory response and also by activation of the immune system. Further studies have confirmed the effectiveness of BCG for the treatment of cancers other than bladder cancer and this treatment needs host immune system for proper functioning [110, 111]. In this type of biological therapy for cancer, live BCG is required for immune system activation and to achieve the effect against the tumor cells direct or close contact of BCG is required. For the treatment effectiveness, the correct amount of BCG is also required [112, 113].

Gene therapy

The conventional treatment methods used for cancer can be challenged by the development of the gene transferring technologies which enable a wide variety of treatments. This technology can provide sophisticated cancer treatment because of the adequate gene expression and delivery systems. Different molecular strategies developed within the framework of this concept include suicide genes, nucleic acids like microRNAs (miRNAs), recombinant DNA, zinc finger nucleases (ZFNs), interfering RNA (iRNAs), clustered regularly interspaced short palindromic repeats/CRIPR-associated protein 9 (CRISPR/Cas), and transcription activator-like effector nucleases (TALENs) [114–116].

Different strategies that have been used in gene therapy for targeting cancer include:

• i.The loss or dysregulation of a gene can be counterbalanced by placing the wild-type tumor suppressor gene in its position [117].
• ii.Genes can be manifested that will help enhancing the sensitivity of the tumor to the radiation therapy/conventional drugs or by enhancing the apoptosis pathway to perform its effects [117].
• iii.Enhancing the efficacy of the immune cells to recognize the tumor cells and help kill them. The use of RNA/DNA antisense technique to stop the functioning of oncogenes [118].
• iv.3.12. Immunoconjugates

Another important technique for cancer treatment is the development of immunoconjugates (Fig. 3). The components of the immunoconjugates include the linker, antibody and cytotoxic agent. The role of these components in cancer therapy is: that the antibody will help in identifying the cancer antigens while the linker and cytotoxic agents will not allow the antibody to separate from the effector [119]. Tumors can be targeted by delivering therapeutic agents directly to them with the help of drugs. For direct delivery of virulent agents in cancer cells Nobel laureate Paul Ehrlich at the turn of the twentieth century suggested the possibility of developing an antibody that will act as a therapeutic molecule [120]. Monoclonal antibodies have strongly linked anticancer substances that are components of the immunoconjugates and act against the cytotoxic agents that cause cancer. Different cancers can be targeted by the immunoconjugates. The examples might be: large cell lymphoma, Hodgkin lymphoma and breast cancer that are targeted by trastuzumab emtansine and brentuximab vedotin immunoconjugates [121–123].

Fig. 3.

A scheme showing targeted action of an antibody–drug conjugate (ADC) against cancer cells. ADC is composed of an antigen-specific antibody, a stable linker, and a potent cytotoxic agent. The conjugate selectively binds to a corresponding antigen receptor expressed on the surface of a cancer cell. Following receptor-mediated endocytosis, ADC is internalized, and subsequent intracellular conditions facilitate the cleavage of the linker; this cleavage releases the cytotoxic agent into the cytoplasm of the cancer cell, where it causes the death of the cancer cell

Oncolytic virus therapy

The oncolytic virus therapy uses oncolytic viruses that help in detecting the surroundings of the tumor and help to decrease the progression of tumor. They have a genetic orientation to recognize particular targets or a natural tropism toward the cancer cells [124]. Oncolytic viruses help to stimulate the immune system to generate an antitumor response which will cause the death of cancer cells [125]. After getting infected by the oncolytic virus the tumor cells display on their surface the major histocompatibility complex class 1 (MHC1) molecules; these molecules help to the immune monitoring and killing the neoplastic cells [126]. The infection of neoplastic cells by oncolytic viruses occurs because of different target substances produced by tumor cells which include nuclear transcription factors such as osteocalcin, prostate specific antigen (PSA), human telomerase reverse transcriptase, cyclooxygenase-2 and other surface markers such as folate receptor, endothelial growth factor receptor, prostate-specific membrane antigen,, Her2/neu, and CD20 [124]. Oncolytic viruses are changed so that they are recognized by the receptors on the tumor cells and they are allowed to replicate selectively in the tumor cells because of the deletion which they contain [127–129]. However, along with their replication ability in the tumor cells they also can attack the neighboring normal cells [127, 130]. In normal cells their pathogenicity could be decreased which is a promising feature when using them as a therapeutic option for destroying tumor cells [131]. The viruses that have been altered to treat the cancer include herpes simplex virus (HSV), adenoviruses and vaccinia [130–132].

Preclinical evidence of biologic therapies

In vitro analysis of potential biologic therapies has shown toxicity and efficacy profiling. Nevertheless, does it work in animals and humans as well? In vitro approach also allows scientific investigations to identify to a certain extent potential adverse effects of new treatments allowing researchers to address these issues before using them in clinical trials. Some of in vitro studies of biologics therapies are discussed below.

In vitro study using adoptive T-cell treatment developed by chimeric antigen receptor (CAR) expression to specifically target epidermal growth factor (EGFR) in NSCLC demonstrated anticancer effects. T-cells of human origin were engineered for the expression of EGFR-CAR by optimization of non-viral piggyBac transposon system. Modified EGFR CAR T-cells had also intracellular 4-1BB-CD3ζ signalling domains and scFv transmembrane domain. In vitro analysis confirmed the expansion capability and proved anti-cancer effects of modified CAR T-cells in a time and antigen-dependent manner suggesting that athis might be promising adoptive immunotherapy in NSCLC [133]. It has been shown a strong expression of CEACAM7 (CGM2) only in pancreas and colon cancer which was used as a potential CAR T-cell target for pancreatic ductal adenocarcinoma (PDAC) treatment [134]. In vitro studies on PDAC tumor sections and patient-derived PDAC cell cultures for CEACAM7 expression were evaluated for the assessment of anti-tumor efficacy of CEACAM7 CAR T-cells. The studies showed that CEACAM7 expression was upregulated in PDAC patient-derived tumors thus confirming that CAR T-cells targeting CEACAM7 may play a significant role in targeting antigens-expressed tumor cells. In vitro analysis identified CEACAM7 as the most probable therapeutic target for PDAC [134–136].

Another option for a potential biologic therapeutic substance that has anti-tumor effect was the non-viral third generation Natural killer group 2 from member D (NKG2D) CAR T cells. To validate this hypothesis an in vitro settings (NKG2D) CAR T was constructed to find out whether it has an anti-tumor potential by assessing its ability to sensitize human colorectal cancer cells. In vitro studies showed that NKG2D CAR T-cells were cytotoxic for colorectal cancer cells in a dose-concentration dependent manner when compared with unmodified T cells. This study also showed that modified NKG2D CAR T-cells secreted more IL-2 and IFN-γ than nontransduced T cells. The survival rate of xenograft model of mice with HCT-116 cells was prolonged and NKG2D CAR T cells significantly suppressed tumor growth and reduced tumor size. The conclusion of in vivo analysis that NKG2D CAR T-cells can potentially be used as immunotherapeutic agent against human colorectal cancer [137]. Many studies with established anti-cancer therapeutics have identified the use of certain substances that inhibit the cell signalling pathways which promote cell proliferation and angiogenesis. VEGF-Trap and Sorafenib are two such inhibitors for which it has been demonstrated their significant role as anti-cancer therapeutics. VEGF-Trap, AVE0005, acts by binding to both VEGF-A and PlGF with higher affinity than monoclonal antibodies and eventually inhibit the activation of cell receptors. In vitro analysis confirmed anti-proliferative activity of aflibercept which completely inhibited VEGF-induced VEGFR-2 phosphorylation [138]. On the other hand, an oral inhibitor of the Raf Kinase (B-Raf, C-Raf)—Sorafenib (BAY 43–9006 targets MAPK and Raf/MEK, extracellular signal-regulated kinases (ERK) signaling pathways and also inhibit VEGFR, PDGFR-, and c-kit [139]. In in vitro settings, sorafenib also showed anti-angiogenesis activity [140]. In the attempts to find other molecules that can be anti-angiogenic and pro-apoptotic and significantly reduce or maybe completely inhibit tumor progression, 2-Methoxyestradiol (2ME2) was found. It is a metabolite of estradiol in humans that prevents the polymerization of tubulin thus damaging the microtubules and eventually resulting in cell cycle arrest [141]. In in vitro studies, 2ME2 resulted in decreased HIF-1α protein levels and it substantially appeared to be a potent antiangiogenic and proapoptotic agent inhibiting cell migration and proliferation [142]. Another inhibitor Lenvatinib, which is a multiple receptor tyrosine kinases (RTK) inhibitor, in in vitro studies showed its antitumor potential against RO82-W-1 cell lines by inhibiting fibroblastic growth factor receptors (FGFR) signaling pathway resulting in decreased tumor cells proliferation and metastasis [143, 144]. Lenvatinib has been approved by FDA for treatment of hepatocellular carcinoma, thyroid cancer, and renal cell carcinoma [145]. Another approach to cancer treatment was the induction and activation of immune cells by using the immunotherapeutic potential of Bacille Calmette-Guérin (BCG) vaccine. Specifically, BCG vaccine was tested for bladder cancer cells and it has been shown that bladder cancer cells which have internalized BCG by micropinocytosis secrete different immune system enhancing effectors like IL-6, IL-8, GM-CSF, and tumor necrosis factor (TNF)-α that might enhance the immune response against cancer and consequently act as an anti-tumor therapeutic agent [146]. Animal models can be helpful in providing initial evidence of the efficacy of new treatment options and they can help to standardize treatment protocols and doses. There are certain factors that play a significant role in tumor progression. For instance, tumor microenvironment plays a fundamental role in the progression of cancer which can be regulated by immune cells (ICs) and vascular endothelial growth factors (VEGF), and as a consequence they might regulate the tumor progression. Some pre-clinical studies have addressed the efficiency of VEGF/VEGF receptor (VEGFR) inhibitors showing that it depends only on their immune-stimulatory responses in tumors by repolarizing immune cells (ICs) to a T helper 1 (TH1) cell phenotype. Some additional factors may also affect their ability to have an effect on tumor microenvironment because it succeeded to escape immune-surveillance during treatment [147–149]. Since angiogenesis plays a major role in cancer progression, to have some therapeutic effects on cancer progression angiogenesis and factors that act to inhibit angiogenesis should be explored as an anti-tumor treatment. One study showed that the combination of checkpoint inhibitors as antiangiogenic therapy, more precisely PD-1 and anti-PD-L1 antibodies, significantly improved the efficacy of cancer treatment. Pre-clinical studies have confirmed that that these therapies can enhance each other’s anti-tumor effects. Anti-PD and anti-PD-L1 sensitize cancer cells and therefore prolong the efficiency of antiangiogenic therapy. Anti-angiogenic therapy improves anti-PD-L1 efficacy by promoting vascular changes like vessel normalization which also facilitates the immune cell infiltration and activity [150]. In the same way, anti-CTLA4 transduced tumor cell vaccine (Gvax) in combination with GM-CSF resulted in greater infiltration and a significant change in the intra-tumor balance of Teffs and Tres. These processes corresponded directly to the tumor rejection by blocking CTL-associated antigen 4 (CTLA 4) which resulted in the initiation of the release of inhibitory control substances having an effect on T cell activation and proliferation and inducing anti-tumor immunity in preclinical studies [143]. Anti-PD-1 and anti-CTLA-4 have independently proven their anti-tumor potential. Further assessment of their anti-tumor effects when used in combination, i.e. the therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), demonstrated significant anti-tumor activity in different cancers, especially metastatic melanoma. Such a combination therapy caused favorable changes in the balance of effector T cells (Teffs) and regulatory T cells (Tregs) within the tumor microenvironment. also resulted in the secretion of proinflammatory cytokines and the activation of tumor specific T-cells [151]. On the contrary to inhibition of factors causing tumor progression, immunotherapeutics like dendritic cells (DCs) which tend to enhance anti-tumor immunity in a highly aggressive brain tumor (glioblastoma) can also be a potential treatment option for cancer. DC vaccines have proven to be a significant step forward in the pursuit of more effective and personalized treatment against glioblastoma [152].

Clinical trials

Clinical trials are most important in testing new treatment options and evaluation of their effectiveness and safety. Successful results of clinical trials are also fundamental for the regulatory approval of new treatments demonstrating their safety and efficacy paving the way for their widespread use. Several biologic therapy options are at the moment in the phase of clinical trials;

An immune-therapeutic, tumor infiltrating lymphocytes (TIL), were in Phase II clinical trials which showed the objective response (OR) in half of the patients with metastatic melanoma who were treated with TIL [153, 154]. For the treatment of recurrent Acute Lymphoblastic Leukemia (ALL) the studies ate trying to establish bispecific CAR T cells for CD22 and CD19 [155]. The cells that lose CD19 antigen can lead to recurrent B-cell ALL but the clinical trials using CD19/CD22 CAR T cells have showed positive results by treating the recurrence of this type of leukemia [156]. Clinical trials have reported that the following oncolityc virus have the potential anti-cancer effects: LOAd703 oncolytic adenovirus given to patients with pancreatic cancer, ADV/HSV-tk oncolytic therapy given to patients with metastatic small cell lung cancer and patients with metastatic triple-negative breast cancer, and GL-ONC1 vaccinia oncolytic virus [157]. Some of the potential candidates for biologic therapy for cancer which are in clinical trials are listed in Table 3

Table 3.

Biological therapeutic drugs under clinical trials

Drug	Drug Type	Drug Class	Disease	Stage of Disease	Trial Identifier
Envafolimab [150]	Antibody	Immune therapy	Advanced cancer/ solid tumor only	Metastatic/ advanced	ClinicalTrials.gov Identifier: NCT02827968
Anlotinib [158]	Small Molecule	VEGFR	Lung cancer—NSCLC	Metastatic/ advanced	Chinese Clinical Trial Registry Number: ChiCTR1900020948
Osimertinib [159]	Small molecule	EGFR	Lung cancer-NSCLC-EGFR-mutant	Metastatic/ advanced	ClinicalTrials.gov Identifier: NCT04965701
Envafolimab [160]	Antibody	Immune therapy	Advanced cancer/ solid tumor only	Metastatic/ advance	ClinicalTrials.gov Identifier: NCT02827968
Durvalumab [161]	Antibody	Immune therapy	Advanced cancer/ solid tumor only	Metastatic/ advanced	ClinicalTrials.gov Identifier: NCT02938793
Trametinib [162]	Small molecule	MEK	Melanoma	Metastatic/ advanced	ClinicalTrials.gov Identifier: NCT02296112
Trametinib Sorafenib [163]	Small molecule	MEK Tyrosine kinase inhibitor	Hepatocellular carcinoma	Metastatic/ advanced	ClinicalTrials.gov Identifier: NCT02292173

Limitations and challenges of biological cancer therapy

Limitations

Biological therapy of cancer is a very promising approach but it has several limitations. Biological therapy has patient specific limited efficacy and resistance and not all cancer patients respond to biological therapies and it does not have in all patients the the same effectiveness. The treatment efficacy, immune response and resistance to biological therapeutics are based on individual patient characteristics, genetics and type of cancer [164]. The immune system, particularly through adaptive immune responses, can adjust to the presence of cancer cells, leading to immunotherapy failure. Tumor cells may evade detection, suppress immune activity, or induce exhaustion in effector T cells, diminishing immunotherapy's therapeutic effects; understanding these adaptive mechanisms is essential for developing more durable and effective treatment strategies [165].

Resistance to biological therapy and limited knowledge about developing resistance mechanisms is a considerable challenge limiting the long-term effectiveness of biologicals as a therapeutic option. Tumors are composed of diverse cell populations with varying genetic and phenotypic characteristics, leading to differential responses to personalized immunotherapies [166]. This complexity in tumor biology often results in resistance mechanisms that can limit the efficacy of these therapies, as certain subpopulations of cancer cells may evade immune detection or adapt to therapeutic pressure [166]. Addressing these challenges is fundamental to improve the precision and durability of treatment outcomes. Over time, tumors may develop resistance to therapies, including immunotherapies, through various mechanisms. These mechanisms include genetic mutations that alter the target molecules of the therapy, immune evasion where cancer cells inhibit or escape immune detection, and changes in the tumor microenvironment that create an immunosuppressive environment. Such resistance can significantly reduce the long-term effectiveness of these therapies, necessitating ongoing research to counteract these adaptive mechanisms.

The tumor microenvironment and its immune-suppressive nature can potentially limit the effectiveness of certain biological therapies such as immunotherapy. Older and immunocompromised patients may have reduced tolerance towards treatment with biologicals. The high cost as well as problems with availability and access to biological therapy are substantial concern when compared with conservative cancer treatment options due to the financial constraints of the healthcare systems.

Clinical implementation: challenges in translating personalized immunotherapies

Despite the promise of personalized immunotherapies, their successful clinical implementation faces significant challenges. Patient selection is critical, as not all patients respond equally to immunotherapy. Biomarker identification is vital to predict treatment response, and the accuracy of these biomarkers directly influences the success of personalized treatment strategies and current efforts focus on refining biomarker panels to include not only genetic mutations but also the tumor microenvironment and immune profiles, as these factors influence how patients respond to immunotherapies [167]. Treatment timing is another fundamental consideration. For personalized therapies to be effective, they must be administered at optimal stages of disease progression. Administering treatment too early or too late in the disease course could limit therapeutic efficacy. Thus, real-time monitoring of biomarkers and adaptive treatment plans are necessary for optimizing the timing of interventions.

Managing side effects poses further logistical and clinical challenges. Personalized therapies, particularly those that engage the immune system, can lead to immune-related adverse events (irAEs), which vary widely among patients. These side effects, such as cytokine release syndrome (CRS) and immune checkpoint inhibitor-related toxicities, can complicate treatment and limit patient eligibility. Strategies to manage these side effects include pre-treatment risk assessments, continuous patient monitoring, and the use of immune-modulating agents to prevent severe adverse reactions. Logistically, the infrastructure required to support personalized therapies—such as real-time diagnostic testing, sophisticated biobanking, and specialized treatment facilities—presents a barrier to widespread clinical adoption. Additionally, cost considerations for both healthcare providers and patients must be addressed to ensure equitable access to these advanced therapies.

Based on recent updates in the literature, overcoming these obstacles will require a multidisciplinary approach that integrates oncologists, immunologists, bioinformaticians, and clinical pharmacologists to tailor treatments effectively and manage the complex interplay of factors involved in personalized cancer therapy. Collaborative efforts across institutions and countries are necessary to standardize protocols and improve the availability of cutting-edge diagnostic and therapeutic technologies.

Conclusion and future perspectives

The increasing number of cancer patients and the limited effectiveness of conventional chemotherapy methods have driven the search for more innovative and effective treatment approaches. Biological therapies for cancer have emerged as promising alternatives due to their ability to target specific molecular mechanisms within tumors. In this review, we have discussed various biological therapies and their effectiveness in targeting different types of cancers, with a focus on the potential of monoclonal antibodies and adoptive cell transfer in personalized medicine. One of the significant challenges in immunotherapy remains the accurate identification of biomarkers that can predict which patients will benefit from specific treatments. Misidentification or a lack of robust biomarkers can lead to ineffective treatments and adverse outcomes. Therefore, ongoing research to develop reliable biomarkers that guide personalized treatment strategies is essential. Identifying new tumor targets and expanding our understanding of cancer biology will enable more precise delivery of biologic agents, advancing the efficacy of immunotherapies.

Techniques such as adoptive cell transfer, including CAR T cells, have shown the ability to enhance immune system function, directly targeting cancer antigens. Similarly, monoclonal antibodies continue to play a critical role in cancer therapy by providing targeted treatment options. However, overcoming resistance mechanisms and minimizing adverse effects remain key areas of focus. Additionally, angiogenesis inhibitors that target specific receptors, DNA- and RNA-based cancer vaccines, and gene therapy approaches offer innovative strategies for treating cancer, although challenges such as safety and efficacy still need to be addressed. The evolution of biological therapies is strongly supported by advances in molecular biology techniques, such as next-generation sequencing (NGS). NGS has improved our understanding of cancer biology, enabling the identification of personalized mutations and the development of tailored treatment options. Personalized therapies, designed to target specific mutations in a patient’s tumor, offer the potential for more precise treatment outcomes with fewer side effects. In conclusion, while significant progress has been made in biological therapies for cancer, continued research is necessary to refine these approaches and address the challenges of resistance and adverse effects. The future of cancer treatment lies in personalized medicine, where therapies are tailored to the individual characteristics of each patient’s tumor, paving the way for improved outcomes and better quality of life for cancer patients.

Author contributions

A.F., A.H.: data curation; formal analysis; investigation; methodology of this study; project administration; resources; software; validation; visualization; writing of the manuscript – original draft; writing of the manuscript – review and editing. R.K., M.I., Z.R.: Investigation; methodology; resources; validation; visualization; writing of the manuscript – original draft; writing of the manuscript – review and editing. J.S.-R.; K.K.; D.C: Conceptualization of the study; data curation; funding acquisition; investigation; project administration; supervision; validation; visualization; writing of the manuscript – original draft; writing of the manuscript – review and editing. All authors listed have made a substantial, direct, and intellectual contribution to the review.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.