The Synergistic Era in Cancer Treatment—Immunotherapy and Personalized Cancer Care

Mohd Wajid Ali Khan^1*Subhash Kumar Tripathi^2*Saravanan Rajendrasozhan¹

• ¹University of Hail, Ha'il, Wales, Saudi Arabia
• ²Seattle Children's Hospital, Seattle, United States

Development and innovation of novel therapies for advanced cancer are based on conventional treatments such as radiotherapies and chemotherapies which lead a diverse array of immune responses. Wang et al. (2024) showed evidence that radiotherapy (RT) can function as an in-situ vaccine. It induces immunogenic cell death (ICD) releasing tumor antigens and damage-associated molecular patterns (DAMPs) that may initiate the activation of immune cells such as dendritic cells. Crucially, by causing DNA damage, RT activates the cGAS (Cyclic GMP-AMP synthase)-STING (Stimulator of interferon genes) pathway, leading to type I interferon production and inducing robust T-cell response. This transformation of the tumor immune microenvironment (TIME) from an immunosuppressive state to an immunologically active narrates the physiological phenomenon for the remarkable a systemic tumor response, where localized irradiation results in the regression of metastatic lesions outside the radiation field. Whereas the same biological processes can induce immunosuppression. RT can upregulate checkpoint proteins like PD-L1, promote the expansion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and cause systemic lymphopenia, thereby counteracting its own immunostimulatory effects. Thus, ensures that RT is not a passive partner but an active immune modulator. The clinical challenge, therefore, is to strategically harness its immunostimulatory potential while reducing its suppressive effect. This can effectively be achieved via combination with immune checkpoint inhibitors (ICIs) Wang et al. (2024). In an extensive study on advanced Non-Small Cell Lung Cancer (NSCLC) by Wang et al. 2024 showed that pembrolizumab with radiotherapy treatment enhanced the patient conditions and lead to improved progression-free survival (PFS) and overall survival (OS) compared to pembrolizumab alone, with notably enhanced distant tumor response rates. The combinational therapeutics lend significant effect on solid tumor treatments. A meta-analysis of phase III clinical trials conducted by Zhang et al. (2024) analysed the role of ICIs as first-line standard therapy for recurrent or advanced cervical cancer. Overall outcome of the study exhibited improvements in both progression-free survival (HR 0.67) and overall survival (HR 0.66) with ICI-based treatments compared to single therapeutic treatments. The positive outcome was observed in patients with higher expression of PD-L1 in tumors and those with histology of squamous carcinoma. Whereas the combination of ICIs with conventional therapies was associated with slight increase in adverse events (AVs) relative to standard therapy alone. These findings emphasize the importance of careful patient monitoring during combination therapy. This also shed light for the need of thorough assessment of toxicity risks before adopting such treatment strategies in clinical practice.In a retrospective study, Wang et al. (2024) investigated the efficacy of combining the antiangiogenic agent anlotinib with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy to improve outcomes in patients with non-small cell lung cancer (NSCLC). The triple combination therapy (AIC: anlotinib, ICI, and chemotherapy) achieved a median progression-free survival of 7.76 months, which was significantly longer by 2.33 months than that observed with the combination of ICIs and chemotherapy alone. These findings proved the significant role of adding anti-angiogenic agents into combination treatment regimens. Notably, even the two-drug combination of anlotinib and chemotherapy demonstrated superior progressionfree survival compared with the ICI-chemotherapy regimen. These findings strongly suggest that for later-line NSCLC patients, the addition of an anti-angiogenic agent is critical to delaying disease progression. Furthermore, the authors reported that the overall risks and toxicities were tolerable and can be controlled. Although the study included small number of sample sizes with single center collection, the study showed the potential of triple therapy as an effective treatment option for NSCLC patients who have not responded to standard conventional treatments. Further randomized controlled trials are warranted to validate these findings and confirm the efficacy and safety of this therapeutic approach.Li et al., (2024) performed a retrospective study and compared the effectiveness of targeted immunotherapy vs targeted therapy alone in the third-line or beyond setting for microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients (n=71) to help identify the beneficial population of combined targeted-immunotherapy. Out of a total of 71 subjects, 31 received targeted therapies alone (TT group), and 40 received combinations of targeted therapy and immunotherapy (TI group). The outcome of the study was that combination therapy improved response rates (20% vs. 3.2%) and controlled disease (82.5% vs. 58.1%), with longer median progression-free survival (4.6 vs. 4.1 months). The most significant outcome of the combinational targeted immunotherapy was observed in patients with lung metastasis alone. These findings suggest that targeted immunotherapy combinations can enhance efficacy in selected MSS mCRC patients. Further studies with larger patient cohorts are still necessary to strengthen reliability and validity.In another retrospective study involving 71 patients, Zhao et al. (2024) investigated whether baseline lymphocyte counts could help identify which hepatocellular carcinoma (HCC) patients would benefit from targeted combination immune therapy. The study showed that both progression-free survival (PFS) and overall survival (OS) improved (p = 0.058 and p = 0.077, respectively) in patients receiving combination therapy with tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors. Notably, patients with high peripheral blood lymphocytes count (PBLC) exhibited better OS and PFS as compared to the cancer patients with low absolute PBLC. These results highlight PBLC could be a routine blood measure which can be use as potential biomarker to identify HCC patients most likely to benefit from TKI and PD-1-based combination therapy.Implementing lymphocyte count as a stratification or decision-making tool could optimize precision therapy and minimize unnecessary toxicity and cost. Additional trials, such as CARES-310 (camrelizumab plus apatinib) and HIMALAYA (durvalumab plus tremelimumab), also showed encouraging efficacy, with the latter achieving an ORR of 20.1%, median PFS of 3.8 months, and median OS of 16.4 months in unresectable HCC. ICIs for the treatment of unresectable advanced HCC patients. In addition, there is also the phase II study of TACE in combination with nivolumab for intermediate-stage HCC (IMMUTACE) and the phase III LEAP-012 (NCT04246177) study of TACE in combination with lenvatinib and pembrolizumab for intermediate stage HCC, which also exhibited better results. However, this rapidly expanding combinational therapeutics is include significant challenges, including the need to identify optimal biomarkers for patient selection, manage unique immune-related adverse events, overcome primary and acquired resistance, and define the most effective sequences and combinations within an increasingly complex treatment landscape. The future of HCC therapy lies in deepening our understanding of the tumor-immune environment to guide these sophisticated, personalized combination approaches.A meta-analysis study by Zhao et al. (2024) evaluates the safety and efficacy on combining concurrent chemoradiotherapy (CCRT) with ICIs in locally advanced cervical cancer (LACC).The combined data suggests that together, CCRT and ICIs may improve objective response rates (ORR) compared to CCRT alone, with an improved disease free survival trend. Whilst these findings are promising, the evidence remains limited, and hence, long-term outcomes and overall safety require further investigation. This study emphasizes the potential of combining immunotherapy with standard LACC treatment to enhance therapeutic efficacy.A systematic review and meta-analysis study evaluated the efficacy and safety of anlotinib in advanced digestive system neoplasms (DSNs). Twenty clinical trials which include 1613 patients, exhibited anlotinib combined with conventional cancer treatments significantly improved shortterm outcomes. Patients' overall survival time increased by 6-month. This study exhibited that the combinational therapy increased the higher incidence of adverse events including hypertension, proteinuria, fatigue, and gastrointestinal disturbances. There were no treatment-related deaths occurred. Subgroup analysis indicated a relatively less effect in advanced gastric cancer. These findings demonstrate anlotinib with other combinational interventions proved as promising therapeutics in DSN treatment (Zhou et al., (2024)). Furthermore, there is more careful risk-benefit assessment needed and further studies to define long-term efficacy and optimal patient selection. Predictive models are essential for several reasons. First, they move clinical practice beyond population-level evidence, these highly important for establishing efficacy. Heterogeneity of treatment effects provide individual patient responses to the treatment may vary. The therapy that offers a modest survival benefit on one patient and entirely ineffective for another. By including variables such as tumor genomics (e.g., PD-L1 status, mutational burden), clinical parameters (e.g., lactate dehydrogenase levels, sites of metastasis), host factors (e.g., baseline lymphocyte count as highlighted by Zhao et al. (2024) in HCC), and specific treatment conditions, these models can classify patients into subgroups most likely to derive benefit. Second, these models are crucial for risk mitigation. As starkly illustrated by the case report of sintilimab-induced agranulocytosis Qin et al. (2024), the potent activation of the immune system by ICIs carries the risk of severe and unpredictable toxicities. Predictive modeling is not solely about predicting efficacy; it is equally about identifying patients at high risk for immune-related adverse events (irAEs). A model that could flag a patient's predisposition to hematological toxicity, for instance, would allow for enhanced monitoring and preemptive management, thereby improving safety.The predicted future of these treatment tools relies on the development of dynamic treatment plan designed by AI, using clinical data derived from the electronic health records of diverse range of patients, multi-omics profiling, and even digital biomarkers. This continuous leaning AI-designed treatment plan will the best use of available therapy and eventually create a 'digital treatment planner' that can simulate the possible therapeutic outcome and side effects of various combinations of drug treatment for a particular patient. The data-driven treatment plan can ensure the individual-specific cancer care and thereby maximize the therapeutic potential of combination of drugs with minimal side-effects. Qin et al. (2024) reported an immune-related adverse events (irAEs) caused by a cancer immunotherapy drug, sintilimab (anti-PD-1 Ab). Sintilimab induced agranulocytosis in a patient with non-small cell lung cancer, which highlight the unpredictable side-effects and limitations in ICI cancer therapy. Although, ICIs treatment is effective in cancer treatment, their mechanism of activating T-cells is primarily related to over-response of the immune system, leading to side effects like autoreactive immune responses, in this case causing life threatening condition by causing severely low levels of white blood cells called neutrophils. Distinguishing the side-effects of chemotherapy from irAEs is challenging and time consuming. To treat the sintilimab-induced agranulocytosis, a high-dose of corticosteroid was administered, which is not usually included in the standard cancer care. The irAEs poses a significant clinical management challenge as it counter-balance the therapeutic benefits of ICIs. The collective evidence confirms a new major shift in oncology, based on synergistic combinational therapies. We are moving decisively from the era of sequential, non-specific cytotoxic treatments to a synergistic era defined by rationally designed combination therapies that strategically harness and augment the host's immune system. The combination of immunotherapy along with chemotherapy, radiotherapy, targeted agents and/or localized treatments has become an effective clinical treatment strategy in treating various cancer, including NSCLC, breast cancer, HCC, and cervical cancer. This new frontier, however, is accompanied by numerous challenges that need to be addressed for tailoring proper cancer treatment. As our therapeutic regimen expands, the principal challenge is the lack of robust, predictive biomarkers to guide selection among numerous combination options.The promising findings regarding baseline lymphocyte counts in HCC and PD-L1 status in cervical cancer are initial steps; the future demands the discovery and validation of multi-analyte signatures that can predict both efficacy and toxicity for specific drug combinations.Optimizing treatment sequencing and timing has become crucial. The superior efficacy of neoadjuvant immunotherapy in some extent showed importance of treatment schedule. Choosing concurrent or sequential delivery in an optimal order of radiotherapy, chemotherapy, and immunotherapy is critical for maximizing synergistic potential and minimizing antagonistic effects.To achieve the greater clinical benefit of innovational therapies, the management of irAEs is essential, which can be achieved by developing standardized, preventive management protocols and predictive models for irAEs.Finally, the issue of 'easily access to everyone' must be focused on. The affordability of the multidrug combination treatment is a significant barrier to widespread clinical use. Drug price control, by the concomitant efforts of researchers, clinicians, and policymakers, is essential to prevent the disparity in cancer care. Looking forward for the future era of combinational therapeutics will be demonstrated by exploiting artificial intelligence and multi-omics data to create dynamic and individualized "digital treatment planners" based on clinical effeteness of the drugs with respect to the patient-specific factors.In conclusion, combinational treatment designed with multi-target approach on the tumor-immune ecosystem will be the future of standard cancer treatment. This promising therapeutic approach has the potential significantly improve quality of life and survivability of cancer patients, effectively transforming cancer into a more manageable disease.Keywords: cancer, immunotherapy, immune check point inhibitors, PD1/PD1-L, combinational therapeutics, digital treatment planners