Cancer Immunotherapy: Successes and Challenges on the Bumpy Route from Scientific Concept to Clinical Reality

Part 1: Cancer Immunotherapy as a Novel Promising Treatment Option

Alessandra Cesano
ESSA Pharmaceuticals
C

ancer immunotherapy – a treatment that harnesses the immune system’s exquisite specificity and “memory” properties to fight cancer – has revolutionized the field of oncology in a way that could not have been anticipated just ten years ago (1).

In the decade following the approval of the first checkpoint inhibitors, immunotherapy has shifted the paradigm for cancer treatment, delivering effective and durable responses for a subset of patients with histologically different types of advanced solid tumors refractory to standard of care (SOC) treatments (1).

More recently, adoptive cell therapies based on administration of chimeric antigen receptor (CAR)-T cells (2), as well as T-cell redirecting bispecific antibodies (3) have further expanded the impact of cancer immunotherapy showing rapid and dramatic responses in patients with refractory CD19+ B-cell malignancies.  

As a result of these clinical successes, cancer immunotherapy is now commonly recognized as the fourth modality of cancer therapy along with surgery, radiotherapy, and chemotherapy. The immune-oncology field is currently investigating how to combine these approaches with conventional SOC agents to improve patient outcomes, or even replacing SOC regimens that are highly toxic and only moderately effective. In this regard, combination of different checkpoint inhibitors (such as anti-CTLA-4 and PD-1/PD-L1 antibodies) has now become SOC for the first-line treatment of patients with melanoma as well as selected patients with non-small cell lung carcinoma (NSCLC) and renal cancers (4, 5, 6).

Checkpoint Inhibitors
Antibodies directed against cell surface molecules involved in the peripheral immune suppression of pre-existing spontaneous anti-tumor immune responses, such as CTLA-4, PD-1, and PD-L1.

Chimeric Antigen Receptor (CAR)-T Cells
Genetically engineered T cells containing proteins that allow the T cells to recognize the specific cancer cells while becoming highly activated to kill them.

T-cell Redirecting Bispecific Antibodies
Antibodies designed to help engaging T cells with one molecular arm and to target malignant cells with the other.

Challenges

Nonetheless, while these clinical successes demonstrate the incredible potential of the immune system to recognize and destroy cancer cells, in practice the vast of majority of advanced cancer patients treated with these approaches do not experience significant and durable clinical response as a result of primary or secondary mechanisms of resistance to these treatments (1). In addition, these immunotherapeutic approaches are associated with the development of unpredictable, unique, and sometimes quite severe toxicities, such as immune-related adverse events, which are considered secondary to either on-target/off-tumor mechanisms and/or off-target inflammation cascades induced by the treatment (7).

Finally, the financial burden of these treatments is quite significant. Costs range from $150,000 for one year of treatment for the checkpoint inhibitors (used as single agents) to $450,000 for the marketed CAR-T cells, practically limiting patient access to these treatments.

On the clinical development side, building on the progress in understanding the complex mechanisms that govern the interface between tumor and host immune system, several new immunotherapy agents targeting different putative mechanisms of primary/secondary immune resistance are currently evaluated in clinical trials, and approved immune-oncology agents are being tested in combination with a variety of different SOC treatments (8). Given the multiple steps involved in anticancer immunity, the potential to enhance cancer immunotherapy via combinations by modulating different biological steps in immunity simultaneously is, at least theoretically, quite broad. It therefore benefits from a rational biology-based approach to identify potentially synergistic combinations.

Checkpoint Inhibitors
Antibodies directed against cell surface molecules involved in the peripheral immune suppression of pre-existing spontaneous anti-tumor immune responses, such as CTLA-4, PD-1, and PD-L1.

Chimeric Antigen Receptor (CAR)-T Cells
Genetically engineered T cells containing proteins that allow the T cells to recognize the specific cancer cells while becoming highly activated to kill them.

T-cell Redirecting Bispecific Antibodies
Antibodies designed to help engaging T cells with one molecular arm and to target malignant cells with the other.

Challenges

Nonetheless, while these clinical successes demonstrate the incredible potential of the immune system to recognize and destroy cancer cells, in practice the vast of majority of advanced cancer patients treated with these approaches do not experience significant and durable clinical response as a result of primary or secondary mechanisms of resistance to these treatments (1). In addition, these immunotherapeutic approaches are associated with the development of unpredictable, unique, and sometimes quite severe toxicities, such as immune-related adverse events, which are considered secondary to either on-target/off-tumor mechanisms and/or off-target inflammation cascades induced by the treatment (7).

Finally, the financial burden of these treatments is quite significant. Costs range from $150,000 for one year of treatment for the checkpoint inhibitors (used as single agents) to $450,000 for the marketed CAR-T cells, practically limiting patient access to these treatments.

On the clinical development side, building on the progress in understanding the complex mechanisms that govern the interface between tumor and host immune system, several new immunotherapy agents targeting different putative mechanisms of primary/secondary immune resistance are currently evaluated in clinical trials, and approved immune-oncology agents are being tested in combination with a variety of different SOC treatments (8). Given the multiple steps involved in anticancer immunity, the potential to enhance cancer immunotherapy via combinations by modulating different biological steps in immunity simultaneously is, at least theoretically, quite broad. It therefore benefits from a rational biology-based approach to identify potentially synergistic combinations.

As such, identifying and developing biomarkers to inform which patients are likely to derive clinical benefit from which immunotherapy and/or be susceptible to adverse side effects – precision immunotherapy – is a compelling clinical and social need.

Predictive Biomarkers as Critical Tools for Effective Precision Immunotherapy

Predictive biomarkers are defined as biomarkers used to identify patient subgroups more likely to benefit from a certain type of therapy.

Despite multiple translational efforts in this regard, to date there are only two clinical-grade predictive biomarkers approved for guiding immunotherapy (specifically for the use of PD-1/PD-L1 checkpoint inhibitors):

  • The measurement by immune-histochemistry (IHC) of the target expression (i.e., PD-L1 expression by tumor cells or immune cells infiltrating the tumor) (9).
  • The measurement of the number of genetic alterations within a tumor genome, such as microsatellite instability (MSI) and tumor mutational burden (TMB), which is considered correlative with mutant protein burden and, thus, with the presence of a spontaneous host immunity against “non-self” neoantigens that can be peripherally modulated through negative physiological regulatory pathways (including the PD-1/PD-L1 regulatory pathway) (10). Of note, both MSI and TMB assays have been approved as companion diagnostics for molecularly-defined, tumor agnostic pan-cancer applications of anti-PD-1 inhibitors for refractory advanced solid tumors (11 , 12). The approval of the former in 2017 was of particular significance, because it represented the first time the regulatory agency approved a cancer treatment based on a common biomarker (or common underlying biology) rather than the location in the body where the tumor originated.

Despite regulatory approval of different PD-L1 IHC assays as companion diagnostics for anti-PD-1/PD-L1 inhibitors in the clinic, the practice to date has been for each drug company developing an anti-PD-1/PD-L1 inhibitor to independently co-develop – often in collaboration with different diagnostic companies – anti-PD-L1 IHC diagnostic assays using different antibodies, platforms, scoring systems, and cutoffs. As a result, the current matrix of these therapeutics and diagnostics represents a complex challenge for testing, reimbursement, and decision-making in the clinic (9).

Beyond these issues with current PD-L1 IHC assays, PD-L1 as a single-analyte biomarker has additional biologic limitations including cellular, spatial, and temporal heterogeneity, all of which contribute to the suboptimal prediction accuracy of this biomarker in the clinic. Similarly, many factors influence TMB assessment including pre-analytic factors (tissue sample fixation and storage), choice of assay (whole-exome-sequencing versus sequencing of defined targeted gene panel size), bioinformatic parameters used for data interpretation, and methods of reporting. Currently only one centralized TMB assay (FoundationOneCDx assay) has been FDA approved as companion diagnostic for the identification of advanced refractory tumors with increased likelihood of responding to a specific anti-PD-1 anti-body (pembroluzimab) (12).

Part II of this article, available in the March issue of Global Forum, will discuss considerations for moving forward.

Back to Issue