Cancer immunotherapy has taken the center stage among different therapeutic options
for the treatment of cancer. While conventional treatment modalities such as surgery,
radiotherapy, and chemotherapy have offered substantial benefit for the eradication
of primary tumors, the incidence of disease relapse remains a commonly encountered
problem. The recent advances in immunotherapy such as utilization of cancer vaccines,
chimeric antigen receptor T cell therapy, and immune checkpoint blockade (ICB) therapy
have fueled renewed interest in the field. Currently, five ICB antibodies are Food
and Drug Administration approved for the treatment of a broad spectrum of tumor types.[1] These therapeutic antibodies have offered long-term durable responses in a subset
of patients with treatment-refractory metastatic cancer. In the current era, our knowledge
and understanding of the mechanisms and pathways that regulate the immune system's
response to cancer has been tremendously enhanced by high-quality researches. However,
there are many areas which are yet to be fully explored.[2] These include lack of prediction of response and efficacy, inadequate biomarkers,
immune resistance, suboptimal study designs, and financial toxicity.[3]
[4]
[5]
[6]
[7] Researchers are working to solve many such obstacles by more targeted treatments,
precision biomarker developments, combination therapies, and immunoprevention to decrease
cancer incidence, relapses, and management costs.[8]
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The immune checkpoint pathway includes a series of cellular interactions that prevent
excessive effector T cell activity under normal conditions to maintain T cell homeostasis.
Immune response is regulated by an exquisite system of checks and balances that enable
protective immunity and tolerance. The effector functions of innate and adaptive immune
cells are controlled by the expression of immune checkpoints on these cells. T cell
activation is based on the two-signal concept as proposed by Lafferty and Cunningham.[12]
[13] The first signal for T cell activation is provided by the T cell receptor (TCR)
expressed on T cells with the peptide/major histocompatibility complex expressed on
the antigen-presenting cell (APC) which confers specificity to the response. The second
co-stimulatory signal is provided by the interaction between CD28 expressed on T cells
with its ligand CD80 (B7-1) and CD86 (B7-2) expressed on APC. Engagement of signal
1 and signal 2 is needed for T-cell activation. Cytotoxic T lymphocyte antigen-4 (CTLA-4)
was identified as a CD28 homolog that possesses potent inhibitory functions. Engagement
of CTLA-4 with CD80/CD86 was capable of limiting the threshold of T cell activation
and duration of the immune response and was responsible for regulating autoimmunity
and inflammation.[12]
[13]
Ligation of the programmed cell death protein (PD-1, also known as CD279) with PD-1
ligand 1 (PD-L1, also known as B7-H1 or CD274) activates a critical immune checkpoint
leading to T-cell dysfunction, exhaustion, and tolerance. Monoclonal anti-PD-1 and
anti-PD-L1 antibodies that block PD-1/PD-L1 interaction can reverse the immune checkpoint
and release the brakes on the T cell responses. The binding of PD-1 to PD-L1 alters
the immune activity by modulating it to inhibit autoimmune diseases or chronic inflammation.[14]
Cancer cells have hijacked the inhibitory checkpoints to evade recognition by immune
cells. PD-L1 is also constitutively expressed in certain tumors and plays an important
role in preventing T cell-mediated killing, thus evading immune attack. These inhibitory
checkpoints are also key mediators of T-cell exhaustion in patients. Besides CTLA-4
and PD-1, there exist a number of inhibitory and stimulatory regulators that can modulate
TCR-mediated signals,[15]
[16]
[17] for example, T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3)
and lymphocyte activation gene-3 (LAG-3). These molecules are, therefore, attractive
targets for removing the inhibition and enabling cytotoxic T cells to attack cancer
cells. PDL1+-expressing tumor cells and APC engage PD-1+ T cells and bring about apoptosis,
anergy, and exhaustion in T-cells. PD-L1 thus acts as a molecular shield to protect
tumor cells from an immune attack.[15]
[16]
[17]
Clinically, PD pathway blockade has demonstrated clinical responses across a spectrum
of solid tumor types and hematological malignancies. The objective response rates
are varied as reported in different clinical trials. The key question is whether there
are good biomarkers that can predict therapeutic responsiveness to these antibodies.
Ongoing efforts to identify predictive biomarkers have examined the expression level
of PD-L1 on tumors to predict clinical response. While in some malignancies PD-L1
expression was an indicator of poor prognosis for patient survival, in others, it
showed no correlation with the clinical response. Considering the limitations of clinical
sampling methods, it appears that PD-L1 expression on tumor cells and immune cells
may not be a definitive predictive biomarker. More recently, tumor mutation burden
has been proposed as a biomarker of response to immune checkpoint inhibitors (ICIs).
There is evidence to support a link between PD pathway blockade and tumor mutation-derived
antigen-specific T-cell responses. A common feature among various cancers, with higher
probability of response to ICIs, is the higher prevalence of somatic mutations in
their genomes, for example, melanoma and non-small cell lung cancer, both these genomically
unstable tumor types are malignancies which show maximum response to anti-PD-1 therapy.[18]
[19] Similarly, cancers with microsatellite instability or mismatch repair (MMR) deficiency
are known to respond to ICIs. MMR deficiency induces frameshift mutations in tumors,
increasing the likelihood of neoantigen expression in these tumors.[20]
However, this model does not hold true in all cases. For instance, renal cell carcinoma
which is a cancer with low tumor mutational burden responds to ICIs.[21] Similarly, human papillomavirus (HPV)-positive head-and-neck squamous cell carcinoma
(HNSCC) has mutation load comparable to HPV-negative HNSCC, but patients with HPV-positive
HNSCC have better outcomes.[22] High level of mutations may not necessarily result in the expression of immunogenic
neoantigens which are capable of generating T-cell responses that will eliminate tumors.
The importance of immune infiltrate as a prognostic marker is gaining a lot of attention.
The location, type, density, and spatial organization of the immune cell infiltrate
in the tumor are becoming increasingly relevant to predict and guide immunotherapeutic
responsiveness.[23] Lymphocyte infiltration in the tumor results from an immune response, which is thought
to improve disease control and might serve as a prognostic biomarker. Hot (inflamed
tumors) tumors are having better prognosis than cold tumors as they are more immunogenic.[24] Immune cells such as myeloid-derived suppressor cells, regulatory T-cells, and M2
macrophages impede immune responses and result in resistance to immunotherapy. Preexisting
tumor infiltrating immune cells and TH1-type chemokines have been shown to correlate
with clinical response to PD-1 pathway.[25]
[26] Current research focuses on identifying epigenetic biomarkers that can establish
which patients will not benefit from anti-PD-1 or anti-PD-L1 monotherapy. Methylation
status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1
expression and mutational load to select patients who will respond to checkpoint blockade
therapy.[27]
Accumulating evidence in preclinical models and patients suggests that gut microbiome
affects the therapeutic efficacy of cancer immunotherapy, particularly, of the ICIs.[28]
[29] Stratification of patients based on the gut microbiome and investigating their immune
responses and clinical outcomes during the course of immunotherapy will be an interesting
aspect to pursue.
As compared to chemotherapy and molecular targeted therapy, a relatively higher rate
of primary resistance to ICIs is observed in patients, which leads to disease progression
or relapse. The mechanisms of resistance are not well understood, but several tumors
related as well as host related factors play a role. These include PD1 expression,
lack of tumor antigen expression/presentation, cellular signaling pathways, tumor
microenvironment, and epigenetic modification. New combination treatment strategies
are being explored to improve the efficacy of ICIs in a broader patient population
without exacerbating the toxic effects.
Another complexity is the heterogeneity of response observed in patients receiving
checkpoint blockade therapy, which includes pseudoprogression where tumor burden or
number of tumor lesions increases initially before decreasing and hyperprogression
where accelerated tumor growth is observed after immunotherapy.[30]
[31] Unlike pseudoprogression, patients with hyperprogression exhibit worst survival
outcomes. This phenomenon is associated with age, higher metastatic load, and prior
irradiation. Murine Double Minute Homolog 2 and 4 (MDM2/MDM4) amplification amplification
and epidermal growth factor receptor aberrations have been shown as potential biomarkers
for hyperprogression after single-agent checkpoint inhibitor therapy.
Cost of Cancer Immunotherapy
The economic sustainability of health-care systems is global.[9] The introduction of ICBs has revolutionized the cancer therapy, and we have a chance
to talk about “indefinite survival” in clinics with preserved quality of life. However,
the financial toxicity is a real concern.[9]
The IMS Health data revealed that, in 2014, U.S. cancer drugs' expenditure touched
$42.4 billion.[8] This is alarming, and implication in low- and middle-income countries is even more.
There is dire need for collaborative efforts among the medical community.[9] We need to predict a priori which patients are likely to have best benefit with these “magic drugs” with least
toxicity; this biomarker-based selection of appropriate patients can substantially
reduce costs.[9] Other cost saving measures could be analysis for cost-effectiveness, and quality-adjusted
life years; policies for drug reimbursement etc.[9] A fraction of patients receiving ICB treatment have prolonged survival benefits,
so this potential outcome may justify treatment costs.[6]
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Indian Scenario: Immuno-Oncology Society of India
Because immunotherapy is in nascent stage in India and majority of the patients cannot
afford ICBs at this point, an interest group conceptualized the Immuno-Oncology Society
of India (I-OSI) for the promotion and advancement of scientific knowledge and research
in immuno-oncology (IO) which helps in the translation of laboratory discoveries to
patient care. The I-OSI will help increasing the awareness among all the stakeholders,
including public, regarding IO in country. It will increase interdisciplinary interactions
among all stakeholders dealing with IO at national and international levels and strive
to develop guidelines that will assist government and nongovernmental agencies in
all matters pertaining to IO. The I-OSI's head quarter is at Tata Memorial Centre,
and all the details regarding the society are available at the website.[32]
Conclusion
The understanding of IO has increased exponentially; however, many impediments are
yet to be overcome. The present hurdles will likely be taken care by smart strategies
including precision immunotherapies, targeted approach with IO, and efficient combinations
with chemo or targeted therapies. There is a need to focus on the prevention aspects
of cancer through immune-based strategies.
