Moving from Cytotoxic Drugs to Leveraging a Patient's Immune System
Over the course of the past decade, research into new therapies in oncology has moved strongly away from both cytotoxic drugs and targeted therapies, and toward approaches making use of the patient’s immune system to attack cancer cells. There are a number of clear advantages to this approach. The human immune system has been honed over millions of years of evolutionary history to protect the body against cellular malfunctions of the sort that lead to malignancy. As a result, the immune system is able to be both more selective and more persistent in its attacks on cancer cells than traditional therapeutic approaches. Because of this, immune therapies tend to have both lower side effect profiles and a greater hope of complete and lasting remission than other treatment methods.
Immune therapies in general can be grouped into three general categories: immune checkpoint inhibitors (e.g. ipilimumab, pembrolizumab), cancer vaccines (e.g. Provenge), and adoptive cell transfer methods (e.g. CAR-T cell therapy). Each of these has its own strengths and weaknesses, and at times there may be synergies available from combining them with each other or with more traditional therapies.
The area receiving the most attention to date has clearly been immune checkpoint inhibitors. Immune checkpoints are signaling mechanisms used by the immune system to prevent it from attacking healthy tissues. Think of them as the secret handshake that causes a roving T-cell to pass by a normal cell without attacking. The ability to use these checkpoints to avoid immune surveillance is one of the key mutations required to permit a malignancy to grow and spread. Checkpoint inhibitors block the action of these signaling mechanisms, unblinding the immune system and permitting it to find and destroy malignant cells. Checkpoint inhibitors have shown dramatic results in a number of diseases, most prominently malignant melanoma and, to a lesser extent, non-small-cell lung cancer.
Cancer vaccines operate on similar principles, seeking to sensitize the immune system to selected tumor antigens and therefore provoke an immune response. This seems like a reasonable approach, but successful cancer vaccines have been few, and results have been limited. There has been renewed interest in this space recently, however, as some researchers have hypothesized that vaccines may have synergistic effects with checkpoint inhibitors. Trials exploring this approach using several different combinations of agents are currently underway.
Finally, in some ways the most promising, but also the most challenging, approach to immunotherapy is adoptive cell transfer (ACT). There are three sub-branches of this technique: tumor infiltrating lymphocyte (TIL) therapy, T-cell receptor (TCR) engineered T-cell therapy, and chimeric antigen receptor (CAR) T-cell therapy. All three share a common root: T-cells which are primed to attack and destroy tumor cells are grown in vitro and then infused into the patient, where they hopefully multiply and establish themselves, destroying any existing tumor cells and then continuing to patrol the body for recurrence.
The differences among the three ACT techniques relate to the amount of genetic engineering required to produce the T-cells in question. With TIL therapy, naturally occurring T-cells which are already actively attacking the patient’s tumors are extracted, multiplied greatly in vitro, and then re-infused into the patient. TCR therapy involves extraction of T-cells from the patient, which are then modified using a retrovirus to be specifically sensitized to the patient’s tumor antigens prior to re-infusion. CAR-TC therapy involves direct genetic manipulation of extracted T-cells to insert an artificial (chimeric) antigen receptor which is specific to the patient’s tumors.
These techniques have shown dramatic results in childhood leukemia and to a lesser extent in lymphoma. They have shown less promising results in most solid tumors, but the reasons behind this (and therefore hopefully the solution to the problem) are an active area of current research.
All immunotherapies present unique challenges in the clinical trials arena. The standard method for determining disease progression in oncology is fairly simple. Any significant increase in tumor burden after the initiation of therapy constitutes progression, and signifies a reason to change therapy. Patients receiving immunotherapy, however, are prone to pseudoprogression—apparent tumor growth followed later by response to therapy, which can be indistinguishable from treatment failure using standard evaluation criteria.
This is due to two unrelated phenomena. First, unlike chemotherapy, the results of immunotherapy may take a significant amount of time to be felt. It may take as much as several weeks for the immune system to rally after the patient begins treatment, and their tumors may continue to grow during this period. In addition, once the immune system does swing into action, one of the first effects may be edema within the tumors, which can look very much like progression on a CT scan. If evaluated using standard criteria, patients experiencing these effects would be judged as having progressed, and would therefore be removed from therapy prematurely.
Jed Wolchok and his collaborators first documented these phenomena in some of the earliest trials of ipilimumab. In 2009, they proposed new response criteria to account for pseudoprogression in patients undergoing immunotherapy. Dubbed the immune-related response criteria (irRC), these guidelines modified standard oncology response criteria in three ways:
- They no longer declared progression at the first detection of new lesions. Instead, new lesions were to be measured and added into the total tumor burden.
- They no longer permitted the declaration of Progressive Disease due to changes in non-target lesions.
- They mandated confirmation of progression. Only after a patient was shown to be progressing on two consecutive scans obtained at least four weeks apart was true progression to be declared.
The irRC, while a valuable contribution to the field, have a number of problematic features. In particular, they are based not on standard RECIST criteria, but rather on the older WHO criteria, which have not been much used since the late 90s. Additionally, the complete elimination of non-target lesion evaluation can lead in many cases to missed true progression. Consequently, after several years of experience with these criteria, a consortium of industry and academic collaborators came together to devise new criteria which would capture the best features of the irRC, while hewing much more closely to standard RECIST criteria. Dubbed iRECIST, these criteria were published in The Lancet in 2017, and have quickly been adopted by most researchers working in this space.
Moving forward, there are many challenges facing researchers both on the treatment front, where matching the numerous newly available treatments and combinations with appropriate indications is a massive task, and on the evaluation front, where the extent to which pseudoprogression is an issue for various treatment methods, and therefore the value of novel response criteria like iRECIST, which trade delayed progression declarations for the majority of patients in order to protect a small minority (between 5% and 20%) of patients from early declaration of progression, is still a topic of intense research. Here at BTR, we hope to continue to be a part of this work, providing expert imaging and evaluation support for the clinical trials community worldwide.