Review of cancer treatment with immune checkpoint inhibitors

In the treatment of solid malignancies, immune checkpoint inhibitors constitute an important breakthrough positively influencing treatment outcomes regarding progression-free (PFS) and/or overall survival (OS), as compared to chemotherapy-based treatment. Immune checkpoint inhibitor treatment involves antibodies generated against the cytotoxic T‑lymphocyte associated protein 4 (CTLA-4), the programmed death receptor 1 (PD-1) or its ligand (PD-L1). Thus, immune checkpoint inhibitors modulate the interaction between tumor cells and cytotoxic T lymphocytes in the tumor environment, which are exhausted in their function. Targeting with CTLA-4 or PD-1 or PD-L1 reverses the exhaustion of cytotoxic T lymphocytes thus leading to the elimination of tumor cells via the re-induction of the “natural” function of the T cell population. Interestingly, some of the clinical results when using anti PD-1 and anti PD-L1 antibodies may be also due to additional effects on T‑cells including their targeting of B7.1 [1‐4].

Whereas anti-CTLA-4 antibodies (ipilimumab and tremelimumab), anti-PD-1 antibodies (nivolumab and pembrolizumab), and anti-PD-L1 antibodies (atezolizumab, avelumab and durvalumab) have produced remarkable results regarding tumor control in many malignancies (albeit in various treatment lines), response is often followed by relapse and disease progression. Conversely, cancer patients who benefit from checkpoint inhibition can achieve long-term benefit and remarkable duration of PFS. Inhibition of CTLA-4 by ipilimumab represents the first compound ever used in immune checkpoint inhibitor treatment to enter clinical routine. Ipilimumab was licensed for use in advanced metastatic melanoma [5]. The second group of drugs for immune checkpoint inhibition were anti PD-1 or anti PD-L1 antibodies which are currently registered by the U.S. Food and Drug Administration (FDA) for metastatic malignant melanoma, non-small cell lung cancer (NSCLC), renal cell cancer (RCC), head and neck cancer (HNSC), urothelial carcinoma and Hodgkin’s lymphoma in various stages of the respective disease and in the context of varying treatment histories [6‐12]. Many other malignancies (e. g. hepatocellular carcinoma, ovarian cancer, mesothelioma, gastric cancer, B‑cell non-Hodgkin lymphoma) are currently under clinical investigation to determine a possible efficacy of checkpoint inhibition [13‐15]. Landmark trials have shown significant improvement of survival rates in many advanced metastatic cancers (e.g. NSCLC, HNSC, metastatic malignant melanoma and renal cell carcinoma), when compared with chemotherapy or, as in RCC,other treatment modalities, such as everolimus in second line.

Indications for immune checkpoint inhibitor treatment are rapidly increasing [16]: while PD-1 and CTLA-4 directed antibodies were primarily registered for the treatment of metastatic malignant melanoma, NSCLC followed quickly with currently nivolumab, pembrolizumab and atezolizumab licensed for second line treatment, and pembrolizumab for first line treatment for patients with NSCLC and PD-L1 expression of >50%. Additional indications currently comprise renal and urothelial cancer, HNSC squamous epithelial cancer and Hodgkin’s lymphoma.

In hematology, the checkpoint inhibitors nivolumab and pembrolizumab have been approved for the treatment of Hodgkin’s disease [17]: Classical Hodgkin’s lymphoma cells show high PD-L1 expression. Clinical studies have been primarily performed in patient groups with relapsed disease after autologous stem cell transplantation ineligible for autologous stem cell transplantation, a relapse after brentuximab vedotin therapy or without this treatment. The outcome was remarkable [18, 19]: overall response rates (ORR) were up to 65% and complete remission (CR) occurred in approximately 20% of patients. Preliminary results from a phase 1 and 2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin’s lymphoma showed ORR of 90% (26/29) and CR of 62% (18/29).

Many clinical studies with checkpoint inhibitors are currently under way to test their efficacy in various other hematologic indications either as monotherapy or, as in the case of multiple myeloma, in combination with immunomodulators, such as lenalidomide and pomalidomide [20].

Further concepts applied in the field of hematologic malignancies look at the combination of immune checkpoint inhibitors with other immunotherapies: primarily, combinations with bispecific T‑cell engaging antibody (BITE/blinatumomab) or with chimeric antigen receptor T cells (CAR-T-cells) [21]. Although both treatments depend on functional T‑cells, immune checkpoint inhibitors could enhance the T‑cell response to make BITE or CAR-T-cell therapy more effective [11, 22, 23]. In childhood relapsed or refractory acute lymphocytic leukemia, the combination of CAR-T-cell immunotherapy and checkpoint inhibition showed an overall remission rate of 82% within 3 months and an OS of 89% at 6 months.

For anti CTLA-4 therapy, some biomarkers have been identified which may be useful for predictive purposes, but none has entered clinical routine or should be used before starting treatment.

Radiologically, tumor size is the easiest parameter for the determination on an effect of any anticancer treatment. Although this also applies to treatment with immune checkpoint inhibitors, there are particular treatment responses, which are not observed in patients receiving other kind of treatments. As immunotherapies do not target directly the tumor cells but the immune system, the time to a measurable tumor response can be variable. Therefore, in some patients the tumors may remain stable in size or even grow slowly over some weeks or even months before they show a decrease in size. In other patients, the infiltration of tumors by inflammatory cells leads to a temporary increase in tumor size. This so-called pseudoprogession is observed in 10–15% of patients with melanomas and in less than 2% of patients with lung cancer and must not be confused with treatment failure. In analogy, even new lesions might become visible during immune checkpoint blockade, which could be the result of an ensuing visibility of previously undetected metastases due to lymphocyte infiltration. To discriminate progressive disease from pseudoprogression, short-term follow-up examinations not earlier than 4 weeks after the examination in which a progression of disease was observed are advised. Thus, the course of disease under treatment with immune checkpoint inhibitors should be monitored by comparing serial and repeated measurement of target lesions before treatment is abandoned, always keeping in mind the biological principles of treatment versus tumor control. This, however, only applies to patients with no clinical deterioration.

For study purposes, a number of response criteria have been developed, the first one being the immune-related response criteria (irRC) published in 2009 [38]. Very recently, new immune response criteria in solid tumors (iRECIST) criteria have been published, which will be used in future prospective trials in addition to conventional response criteria [39, 40].

Immunotherapy by checkpoint inhibition can cause immune-related adverse events (irAEs) in a considerable number of patients due to the induction of overstimulation of immune reactivity or to the generation of outright autoimmune phenomena [41]. With CTLA-4-inhibition, such side effects are observed in up to 7 patients out of 10, while with PD-(L)1 inhibitor treatment, these occur in only 2–3 out of 10 [42]. As immunotherapy in cancer is assumed to activate the tumor-directed T‑cell response by T‑cells infiltrating the primary tumor and its metastases, this therapeutic intervention can also cause irAEs in all types of tissues. These irAEs may include the induction of diarrhea or the emergence of ulcerative colitis or Crohn’s disease, Hashimoto’s thyroiditis, autoimmune hepatitis, uveitis and hypophysitis which can be life-threatening complications if not recognized and treated appropriately [41, 43, 44].

With rash and pruritus often occurring as the first side effect of anti CTLA-4 treatment, liver toxicity, diarrhea, colitis and hypophysitis tend to appear later. In PD-(L)1 inhibition, most common irAEs are cutaneous and gastrointestinal, less common endocrine, hepatic, pulmonary and renal. Combination of checkpoint inhibitors and duration of therapy cause more severe adverse events typically associated with those encountered during CTLA-4 immune checkpoint inhibition.

In patients receiving immune checkpoint inhibition treatment, every symptom has to be suspected to represent a sign of a possible irAE, and patients should be informed that they should contact the hospital once a possible side effect occurs. Similarly, the patients’ general practitioners should have basic information about irAEs. Early diagnosis and onset of treatment can prevent the development from grades 1–2 to grades 4–5 toxicities. At the hospital, an interdisciplinary team should be ready to assess and manage side effects of immunotherapy according to published management algorithms. While grade 1, irAEs should be managed symptomatically under continued PD-(L)1 inhibition, grades 2 and 3 toxicities necessitate delay of treatment plus the addition of 1–2 mg prednisone/kg body weight with tapering to a dosage of below 10 mg. Grade 4 events and recurrent grade 3 events should cause permanent discontinuation of PD-(L)1 inhibition [45, 46].

When following patients under immune checkpoint inhibitor treatment, it became clear that primary and adaptive resistance to immunotherapy might occur which limits the efficacy of treatment. This calls for concepts to maximize the clinical benefit of immune checkpoint inhibitor treatment by the combination with either other immunotherapy, with chemotherapy, with radiotherapy or with targeted therapies using tyrosine kinase inhibitors. For all of these therapeutic approaches, an abundance of clinical trials in a similar abundance of clinical scenarios and diseases are under way. Aims are to not only increase the activation and function of immune cell-associated tumor cell destruction, but also to widen the current concept to other immune cells including T regulatory cells, myeloid-derived suppressor cells and neutrophils, and, finally, make tumors more immunogenic and induce their infiltration by immunocompetent cells. Overcoming resistance mechanisms will be the key for the obtainment of an enhanced efficacy of immunotherapy in cancer [47].

Primary and intrinsic mechanisms of resistance or mechanisms of adaptation as well as secondary or acquired resistance are the limiting factors for immune checkpoint inhibitor treatment. Thus, gene editing with amplification of PD-L1 in malignant cells appears to occur early and makes malignant cells prone to respond to PD-(L)1 inhibitors, whereas the loss of PD-L1 seems to be the cause of resistance to treatment occurring in some patients. Thus, future strategies should not only address the malignant cells themselves but also their microenvironment and the function of immunocompetent cells [48, 49]. These strategies are given here:

The actual status and future perspectives of immunotherapy in cancer depend on the access of patients to these innovative treatments. Even in the most affluent member states of the EU, there are considerable differences in this field. With currently 28 EU member states and their 28 various healthcare and reimbursement systems and 28 various interpretations of the EU Cross-border Directive make access to checkpoint inhibitor treatment complex and diverse. New pricing models could be a future way for reimbursement in order to simplify the access to this important class of drugs [59‐61]. The involvement of patients and patient advocacy groups must become the norm in HTA assessment which should serve the patients to get access to innovative drugs, as outlined in the magnitude of clinical benefit scale generated by the European Society for Medical Oncology [62].