Immunotherapy in the current era: Transforming the landscape of cancer treatment

Aditya Dhanawat; Kunal Jobanputra; Amit Joshi

doi:10.25259/IJMR_376_2025

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Perspective

162 (

2

); 252-255

doi:

10.25259/IJMR_376_2025

Immunotherapy in the current era: Transforming the landscape of cancer treatment

Aditya Dhanawat, Kunal Jobanputra, Amit Joshi^,*

Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India

* For correspondence: dramitjoshi74@gmail.com

Received: 2025-02-08, Accepted: 2025-02-13, Epub ahead of print: 2025-09-26, Published: 2025-10-10

Licence

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Cancer remains the leading cause of death with an estimated annual incidence of 19.97 million and 9.74 million cancer-related deaths worldwide as per GLOBOCAN-2022¹. Most of the cancer-related deaths are due to lung cancers, followed by colorectal and liver cancers. The annual cancer-related incidence and deaths in India are 14.1 lakhs and 9.1 lakhs, respectively, and most cancer-deaths are due to breast cancer, followed by oral cavity and cervical cancers². The rise of immunotherapy has resulted in a paradigm shift in oncology and emerged as one of the most transformative approaches in cancer care over the past decade. James Allison and Tasuku Honjo were awarded the Nobel Prize in Medicine in 2018 for their work on immunotherapy³. We aim to provide a brief overview of cancer treatment in the current era of immunotherapy.

Mechanisms of immune evasion and immunotherapy

Previously, the treatment of cancer involved cytotoxic chemotherapy, which would non-specifically attack both cancer and non-cancerous cells, causing significant adverse events. Immunotherapy focuses on enhancing the ability of the immune system to detect and attack cancer cells by overcoming the mechanism of immune evasion adopted by cancer cells. This specifically targets and eliminates cancer cells while minimising the attack on surrounding healthy tissue. The domain of immunotherapy is largely comprised of the immune checkpoint inhibitors (ICIs).

Immune checkpoints are critical regulatory pathways that modulate the immune response to maintain self-tolerance and prevent autoimmunity. Tumour cells suppress T-cell activity by inhibiting the immune checkpoint pathways and prevent immune surveillance from recognising cancer cells⁴. The most prominent mechanisms by which cancer cells adopt immune evasion are as follows⁵:

(i)

Programmed Cell Death Protein 1 (PD-1) and PD-L1 pathway: The PD-1 receptor on activated T cells binds to PD-L1 on tumour cells to suppress antitumour immunity. Blockade of this pathway with PD-1 (nivolumab, pembrolizumab) or PD-L1 (atezolizumab, durvalumab) inhibitors restores T-cell–mediated immune responses.
(ii)

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) pathway: CTLA-4, expressed on T cells, competes with the co-stimulatory receptor CD28 for binding to CD80/CD86 on antigen-presenting cells, thereby inhibiting T-cell activation. CTLA-4 blockade with agents such as ipilimumab enhances T-cell activation by preventing this interaction.
(iii)

T-cell Immunoglobulin and Mucin-domain Containing-3 (TIM-3) pathway: TIM-3 on T cells binds to galectin-9 on tumour cells, inducing T-cell exhaustion and immune suppression. Ongoing clinical trials are investigating TIM-3 inhibition as a potential immunotherapeutic strategy.
(iv)

Lymphocyte Activation Gene 3 (LAG-3) pathway: LAG-3 is an inhibitory receptor upregulated on exhausted T cells; its interaction with MHC class II on tumour and dendritic cells suppresses T-cell activity. Multiple clinical trials are evaluating LAG-3 inhibitors.

Melanoma

Immune checkpoint inhibitors have significantly improved long term outcomes and prognosis in patients with advanced melanoma who previously had limited options (Table). Nivolumab plus ipilimumab resulted in a median survival of around 72 months as compared to 36 months for nivolumab alone in advanced melanoma⁶. In stage III resected melanoma, adjuvant pembrolizumab improved 7-year recurrence-free survival (RFS) by 14 per cent⁷.

Table. Summary of landmark trials on immunotherapy

Trial name	Indication	Experimental arm	Control arm	Outcomes
CHECKMATE-067	First-line advanced melanoma	Nivolumab plus Ipilimumab	Nivolumab plus placebo Ipilimumab plus placebo	Median OS Nivolumab+Ipilimumab – 71.9 months Nivolumab – 36.9 months Ipilimumab – 19.9 months
KEYNOTE-054	Stage III resected melanoma	Pembrolizumab	Placebo	7 yr RFS 50% vs. 36%
KEYNOTE-189	First-line metastatic non-squamous NSCLC	Pembrolizumab plus chemotherapy	Chemotherapy	Median OS 22 vs. 10.6 months
CHECKMATE-227	First-line metastatic NSCLC with PD-L1 CPS> 1%	Nivolumab plus ipilimumab	Chemotherapy	Median OS 17.1 vs. 14.9 months
CHOICE-01	First-line metastatic NSCLC	Toripalimab plus chemotherapy	Chemotherapy	Median PFS 8.4 vs. 5.6 months 2-yr OS 51.2% vs. 33.9%
IMPOWER-133	First-line ES-SCLC	Atezolizumab plus chemotherapy	Chemotherapy	Median OS 12.3 vs. 10.3 months
CASPIAN	First-line ES-SCLC	Durvalumab plus chemotherapy	Chemotherapy	Median OS 12.9 vs. 10.5 months
KEYNOTE-048	First-line HNSCC	Pembrolizumab alone (PD-L1 CPS >20%) Pembrolizumab plus chemotherapy (PD-L1 <20%)	Chemotherapy	Median OS (PD-L1 CPS >20) 14.9 vs. 10.8 months (Overall population) 11.5 vs. 10.7 months
JUPITER-02	First-line metastatic NPC	Toripalimab plus chemotherapy	Chemotherapy	Median PFS 21.4 vs. 8.2 months Median OS Not reached vs. 33.7 months
CLEAR	First-line advanced RCC	Pembrolizumab plus Lenvatinib	Sunitinib	Median PFS 23.9 vs. 9.2 months 3-yr OS 66.4% vs. 60.2%
CHECKMATE-9ER	First-line advanced RCC	Nivolumab plus Cabozantinib	Sunitinib	Median OS 49.5 vs. 35.5 months
KEYNOTE-522	Early-stage TNBC	Pembrolizumab plus chemotherapy	Chemotherapy	5 yr OS 86.6% vs. 81.7%
KEYNOTE-355	First-line metastatic PD-L1 positive TNBC	Pembrolizumab plus chemotherapy	Chemotherapy	Median OS (PD-L1 CPS >10) 23 vs.16.1 months
CHECKMATE-901	First-line advanced urothelial carcinoma	Nivolumab plus chemotherapy	Chemotherapy	Median OS 21.7 vs. 18.9 months
JAVELIN BLADDER-100	First-line maintenance after chemotherapy in advanced urothelial carcinoma	Avelumab	Placebo	Median OS 23.8 vs.15 months
EV-302	First-line advanced urothelial carcinoma	Pembrolizumab plus enfortumabvedotin	Chemotherapy	Median OS 31.5 vs.16.1 months

OS, overall survival; RFS, recurrence free survival

Lung cancer

In advanced untreated NSCLC with PD-L1 ≥50 per cent, pembrolizumab monotherapy prolonged median overall survival (OS) by 13 months vs. chemotherapy. In metastatic NSCLC irrespective of PD-L1 status, adding pembrolizumab to chemotherapy improved median OS from 10.6 to 22 months^8,9. In metastatic NSCLC with PD-L1 >1 per cent, nivolumab plus ipilimumab resulted in 5-year OS of 24 per cent as compared to 17 per cent for nivolumab alone and 14 per cent for chemotherapy alone¹⁰. Neoadjuvant pembrolizumab resulted in improvement in median event-free survival (EFS) from 18.3 months to 47.2 months in non-metastatic NSCLC¹¹. Similarly, perioperative nivolumab improved 18-month EFS from 50-70.2 per cent¹². Addition of atezolizumab or durvalumab to chemotherapy has shown significant survival benefit in extensive stage small cell lung cancer (ES-SCLC)^13,14.

Head and neck cancers

Pembrolizumab has been proven to have significant long-term OS benefits either alone (PD-L1 CPS >20) or with chemotherapy (PD-L1 CPS <20) over chemotherapy alone in recurrent or metastatic head neck squamous cell carcinoma (HNSCC)¹⁵. Addition of toripalimab to chemotherapy in metastatic nasopharyngeal carcinoma (NPC) has shown improvement in median PFS and OS¹⁶.

Kidney cancer

Immunotherapy has been a success story in patients with metastatic kidney cancer who are generally resistant to cytotoxic chemotherapy. Pembrolizumab plus lenvatinib or nivolumab plus cabozantinib are approved first-line treatment options in this setting^17,18.

Breast cancer

Pembrolizumab plus chemotherapy has shown survival benefit in early stage and metastatic triple negative breast cancer (TNBC) with PD-L1 CPS >10^19,20.

Urinary bladder cancer

Nivolumab has been approved in adjuvant setting as well as in combination with chemotherapy in advanced urothelial carcinoma²¹. In patients who responded to first-line chemotherapy alone, avelumab maintenance improved median OS by 8.5 months²². Recently, pembrolizumab plus enfortumabvedotin showed 15 months survival benefit over chemotherapy in the first-line metastatic setting²³.

Challenges with Immunotherapy

ICIs portend risk of immune-related adverse events (irAEs) such as skin rashes, endocrinopathies, colitis, hepatitis and pneumonitis^24,25. These irAEs may be mild to life-threatening. Recognition of these irAEs may be challenging as they often masquerade other benign conditions. In patients with co-existing auto-immune conditions, use of ICIs requires careful monitoring and low threshold to discontinue therapy.

The efficacy of ICIs is largely dependent on tumour microenvironment. Presence of immune-suppressive cytokines, T-regulatory cells and tumour associated macrophages (TAMs) affect the function of T-cells leading to reduced efficacy of ICIs.

Many patients do not respond to ICIs due to primary resistance (low tumour mutational burden or insufficient antigen recognition, immune cell infiltration or activation), secondary resistance (alterations and mutations in immune pathway) or clonal evolution (proliferation of resistant clones of cancer cells).

There is a lack of a reliable biomarker that can predict which patients will benefit from immunotherapy. Better patient selection requires a robust biomarker and one which would predict patients at risk of irAEs.

The exorbitant costs (despite patient assistance programmes) result in significant financial burden on patients in low- and middle-income countries where patients do not have adequate insurance coverage. In a study of Tata Memorial Hospital from Mumbai, the accessibility of ICIs in India stands at less than 3 per cent²⁶.

Financial support & sponsorship

None.

Conflicts of Interest

None.

Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation

The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.

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