Immune Checkpoint and Ovarian Cancer

Many scientists and biotechnology companies had given up on the idea of cancer immunotherapy in 1990s. Almost a decade after first detection of T cell suppression effect of CTLA4 the identity of its antibody was established. While they are found effective in many cancers including melanoma, lung cancer etc. immune checkpoint inhibitors have lent an important measure to manage recurrent and refractory ovarian cancer. This subject needs constant updating specially for students of ovarian cancer who are looking at this avenue of cure with much hope. A search for immune checkpoint in ovarian cancer till date was done through pubmed (40 publications, important are cited here) and Google including FDA website to enumerate recent trial effort in this field for recurrent ovarian cancer. Whereas Pembrolizumab is having highest number of trials all pathways are tried, newer combinations like one with PARP inhibitors are emerging. As a new development this subject is experiencing rapid progress and multiple avenues are opening up. However, there are many hurdles to overcome.

Keywords: CTLA4; Immunotherapy in ovarian cancer

Although the idea, called “cancer immunotherapy”, is very appealing and has previously been shown to work in several mouse models of cancer, it has in general been very difficult to translate cancer immunotherapy approaches in human. Because of this frustration, by the 1990s, many scientists and biotechnology companies had given up on the idea of cancer immunotherapy. Eight years after first detection T cell suppression effect of CTLA4 the identity of the antibody molecule was established. Antibody to CTLA4 could increase T cell which in turn destroys cancer cell. This started a completely new age of tumor immunology. Besides CTLA4 many immune checkpoints are now shown which pave new ways in manipulation of immunological control over malignant tumor cells. It has lent an important measure to manage especially recurrent and refractory cancers and those cancers where there is an unmet need like recurrent melanoma, renal cell carcinoma and recurrent ovarian cancer. As a new development this subject is experiencing rapid progress and multiple avenues are opening up. Though there are many hurdle to overcome this needs constant updating specially for students of ovarian cancer who are looking at it with much hope.

More than three decades back T cell infiltration was noticed in ovarian cancers [1]. In 2003 Zhang et al appreciated their role in improved survival. They observed at least 60% benefit in 5 year survival in a cohort of 74 patients. They were treated to obtain complete clinical response after debulking and platinum-based therapy. CD3+ T cells within their tumor and IFN-γ plus macrophage-derived chemokines made the difference [2]. Reason of such heterogeneity is still unclear though subject has grown hugely and gained much strength. Regulatory T-cell subsets (CD4+) had confusing immune suppressing role. However, improved survival is noticed in patients who had higher numbers of intraepithelial CD8+ T cells compared with patients without intraepithelial CD8+ T cells (median survival 55 vs 26 months) [3,4]. Strong positive correlation was observed between levels of CD8+ T cells and granzyme B within tumors [5]. MHC related interferon regulatory factor (IRF)-1 and metastasis related chemokine receptor (CXCR) are the two genes differentially expressed in tumors with high versus low CD8+ T-cell infiltration. Heterogeneity in the tumor microenvironment among patients with EOC, and various immune cell populations those have been associated positively or negatively with clinical prognosis, included tumor-infiltrating lymphocytes (TILs), [6] myeloid-derived suppressor cells [7], and tumor-associated macrophages [8].

Tumour infiltrating lymphocytes (TILs) express the negative regulatory immune receptor, programmed cell death 1 (PD-1), [9] which were upregulated on T-cell activation and suppresses T-effector functions. Several cellular populations, including cancer cells and tumor-associated myeloid cells, express its ligand PD-L1 [10-13]. Expression of PD-L1 by tumors has been associated with decreased intraepithelial TILs and poor overall survival in EOC [13].

In an immune-competent murine model of EOC, PD-1 and PD-L1 blockade has led to eradication of tumors through the expected reprogramming of the tumor microenvironment, [14] which suggested potential benefit from PD-1/PD-L1 inhibition for patients with EOC. The attenuation of T cell function by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) was also noticed in EOC [15]. Although the binding of peripheral membrane proteins B7-1 or B7-2 to CD28 provides an important costimulatory signal, the engagement of CTLA-4 by these ligands induced cell cycle arrest and diminished cytokine production [16-18].

Documented effort to test ovarian cancer started with Hodi et al [19] who gave two patients a single infusion and then nine cases [20] upto 11 infusion of 3 mg/kg ipilimumab after an autologous ovarian tumor cell vaccine transduced with granulocyte-macrophage colony-stimulating factor (GVAX). Only three patients had SD of >2 months.

A phase 2 clinical trial of ipilimumab in relapsed platinum-sensitive ovarian cancer with measurable disease is ongoing though not recruiting any more (NCT01611558). Some trials either in post transplantation or along with other checkpoint molecules like nivolumab and pembrolizumab are recruiting. There are other two trials which are either suspended or terminated. The PD-1 antagonist nivolumab is tested at 1 or 3 mg/kg every 2 weeks in 18 patients with relapsed platinum-resistant disease regardless of PD-L1 expression; there was a 17% overall response rate (ORR) and a 44% disease control rate (DCR=CR+PR+SD), with 2 CR, 1 PR, and 5 patients with SD [21] A phase 1b study tested the PD-1 antagonist pembrolizumab at 10 mg/kg every 2 weeks in 26 patients with heavily treated PD-L1+ ovarian cancer chemotherapy [22]. There was a durable ORR of 11.5%, and a DCR of 34.6%, with 1 CR, 2 PR, and 6 patients with SD. Now pembrolizumab has highest number of clinical trials in ovarian cancer. The PD-L1 antagonist avelumab was given at 10 mg/kg every 2 weeks in a phase 1b study of 75 patients with platinum-resistant or chemotherapy-refractory ovarian cancer regardless of PD-L1 expression [23] with an ORR of 10.7%, and a DCR of 54.7%. A phase 1 study of another PD-L1 antagonist, BMS-936559, revealed one objective response in 17 ovarian cancer patients [24]. A summary of trials in ovarian cancer is given in Table 1.

As a whole benefit in OS with ICIs was significant in both younger and older patients with a cut-off age of 65-70 years in a total of 5265 patients from nine RCTs of ICI [25]. When patients are dichotomized into younger and older groups with an age cut-off of 65-70 years, ICIs improved OS in both younger (HR, 0.75; 95% CI, 0.68-0.82) and older (HR, 0.73; 95% CI, 0.62-0.87) groups. An improvement in PFS was observed in younger (HR, 0.58; 95% CI, 0.40-0.84) and older (HR, 0.77; 95% CI, 0.58-1.01) patients. Subgroup analyses according to ICI and tumor type showed a consistent survival benefit in both younger and older groups except for the subgroup of older patients treated in 4 trials of anti-programmed cell death protein-1 (PD-1) monoclonal antibody (HR, 0.86; 95% CI, 0.41-1.83).

These drugs generally contain warnings with regard to increased risks of severe immune-mediated inflammation of the lungs, the colon, the liver, the kidneys (with accompanying kidney dysfunction), as well as immune-mediated hypothyroidism and hyperthyroidism.

In clinical trials for melanoma, the following side effects occurred in more than 10% of subjects and more frequently than with chemotherapy alone: rash and itchy skin, cough, upper respiratory tract infections, and peripheral edema. Other clinically important side effects with less than 10% frequency were ventricular arrhythmia, inflammation of parts of the eye (iridocyclitis), infusion-related reactions, dizziness, peripheral and sensory neuropathy, peeling skin, erythema multiforme, vitiligo, and psoriasis. In clinical trials for lung cancer, the following side effects occurred in more than 10% of subjects and more frequently than with chemotherapy alone: fatigue, weakness, edema, fever, chest pain, generalized pain, shortness of breath, cough, muscle and joint pain, decreased appetite, abdominal pain, nausea and vomiting, constipation, weight loss, rash, and itchy skin. Levels of electrolytes and blood cells counts were also disrupted.

It is evident from discussion that much obstacles are remaining in establishing immuno therapy in ovarian cancer as response rate is low and no FDA approval is in the offing. Expectedly Professor Maurie Markman has commented at the 33rd Annual Chemotherapy Foundation Symposium “The checkpoint inhibitors are not ready for prime time yet in ovarian cancer. It’s not because there’s evidence that they don’t work — it’s just that there’s no evidence at all,” But that will in no way undermine this important effort of treating first the relapse and refractory cases. It will certainly and find out the hindrance and to make best use of developed knowledge to find ways to subvert shortcoming of this important measure of treatment.