Immuno-oncology has advanced rapidly, with the introduction of immune checkpoint inhibition and effective adoptive T-cell therapies. As these agents rush through development, several questions remain regarding the optimal patients for treatment and the next steps for further improving outcomes.
Madhav V. Dhodapkar, MBBS
Immuno-oncology has advanced rapidly, with the introduction of immune checkpoint inhibition and effective adoptive T-cell therapies. As these agents rush through development, several questions remain regarding the optimal patients for treatment and the next steps for further improving outcomes, according to Madhav V. Dhodapkar, MBBS, at the 2016 International Congress on Hematologic Malignancies.
“Things have changed in the past 5 years, to the extent that immuno-oncology has now become perhaps the fastest moving component of cancer therapeutics, and I would argue, hopefully a major component of cancer prevention, as we go along,” said Dhodapkar, Clinical Research Program Leader, Hematology Program, Yale Cancer Center.
There are several tumor properties that create therapeutic challenges, many of which can be addressed using immuno-oncology. Specifically, Dhodapkar explained, immunotherapy is an ideal therapy for cancer, since it can overcome the proliferative nature of the disease, it's genetic complexity, heterogeneity, and characteristics that a tumor shares with normal tissue.
“What you really need is an approach that has the ability to survive as long as the cancer cell does and has the ability to evolve with the cancer,” Dhodapkar said. “Essentially, the immune system provides all of these properties, which makes this a living drug, if you will, against multiple targets.”
There are several approaches to immuno-oncology, including vaccines against antigens, antibodies against specific targets, and the genetic modification of T-cells. At this point, successful immunotherapy approaches have focused almost exclusively on improving the priming and activation of the immune system and the direct killing of cancer cells; however, a number of other approaches can still be exploited.
Early in the carcinogenesis process, there is evidence that the immune system is capable of detecting premalignancies. This concept can be used to help prevent cancer, believes Dhodapkar. “If you try to manipulate the host response at an early stage, you can modify the evolution to the malignant state,” he said.
There are several targets available for immunotherapy, which can be utilized on an individual basis in each unique type of cancer. The main targets include mutation-derived neoantigens, viral antigens, and cancer stem cell associated antigens. This approach is ideal for tumors with high mutation burdens, like melanoma and other solid tumors, Dhodapkar believes.Neoantigens, which arise as a result of tumor-specific mutations, are one of the most attractive targets for immunotherapy, according to Dhodapkar. This approach became feasible with the sequencing of the genome, which revealed several mechanisms across types of cancer. A therapy against neoantigens has the benefit of being tumor specific, while capitalizing on preexisting high affinity T-cells and a lack of tolerance concerns.
“One of the advantages of targeting neoantigens is that you can target so-called 'non-druggable' mutations,” said Dhodapkar. “In an individual patient, we can create a vaccine, provide that vaccine with checkpoint blockade—or perhaps expand neoantigen T-cells ex vivo—and, all of these approaches are ongoing.”
Other targets include those involved in the maintenance of stemness in cancer cells. One such example is the stem cell transcription factor SOX2, Dhodapkar said. Similarly to the neoantigens, this approach allows access to traditionally “undruggable” targets.A new treatment selection system may need to be considered that looks at T-cell activity, regardless of the type of tumor. For this, Dhodapkar proposed two groups of patients, based on their T-cell characteristics: one with low levels of T-cells and the other with high T-cell activity.
In the case of the T-cell poor tumors, a combined treatment approach that utilizes a vaccine therapy with immune checkpoint blockade may be ideal, notes Dhodapkar. This is the category where most hematologic malignancies are likely to fall, since they have a lower mutation burden. However, for those with highly immunogenic tumors, such as melanoma, a checkpoint inhibitor alone may be sufficient, he noted.
Simply eliciting an immune response is not often sufficient to kill the tumor, warned Dhodapkar. This is due to the immune system brakes, such as the PD-1/PD-L1 pathway, which suppress the immune response. This realization led to the discovery of the immune checkpoint inhibitors, which have revolutionized the treatment landscape for patients with cancer.
“This is a pathway that helps control an active immune response against the tumor, and therefore blockade against this pathway has led to pretty impressive rates of activity against many, many cancers now,” said Dhodapkar. “There is pretty impressive activity in the context of Hodgkin's lymphoma.”
Early data have shown that single-agent treatment with either the PD-1 inhibitor nivolumab (Opdivo) or pembrolizumab (Keytruda) elicited high response rates for patients with Hodgkin lymphoma. In these studies, a majority of patients who received several prior therapies experienced long-lasting responses.
“One of the ways that this disease differs from others is that the PD-L1 expression is driven primarily through a combination of an Epstein-Barr virus infection and cytogenetic changes that lead to overexpression of the PD-L1 locus,” said Dhodapkar. “It has become clear that the clinical activity of the checkpoints depends on preexisting immunity of these tumors but that responses can be very durable.”
While single-agent checkpoint inhibitors work well in tumors with high T-cell activity, other approaches will be required for low mutation, non-inflamed tumors. Studies have assessed combined checkpoint blockade with some success, specifically for the combination of nivolumab and the CTLA-4 inhibitor ipilimumab (Yervoy). Additionally, there are a host of other immune checkpoints that have not yet been explored, Dhodapkar explained.
Other approaches for non-inflamed tumors include T-cell activation using vaccines or agonistic antibodies, such as those against CD137, or adoptive T-cell therapies, such as chimeric antigen receptor (CAR)-modified T-cells. Additionally, Dhodapkar explained, immunomodulation techniques, targeting cancer stem cells, and enhancing T-cell infiltration with oncolytic viruses could also prove beneficial.One hurdle currently facing checkpoint inhibition is the differences in tumor microenvironments across tumor sites. Biopsies have found that a tumor in one location could express PD-L1 while a metastases in another location does not. This variation from site-to-site is particularly a concern for treating hematologic malignancies, noted Dhodapkar.
An adoptive T-cell therapy approach could help address variations between sites. One of the most popular approaches for this currently are CAR-modified T-cell therapies. While these therapies have shown promising signs of early efficacy in acute lymphoblastic leukemia, they are associated with cytokine release syndrome, encephalopathy, and on target toxicity.
“The important thing to realize is that as it stands right now no two CAR T-cell therapies seem to be the same. Really, every CAR T-cell is a little different, and not just because they target different antigens,” said Dhodapkar. “They use different constructs, different vectors, type of T-cells they target, and what kind of lymphodepleting therapy they are using.”
The use of modified dendritic cells and adjuvants has shown some success is the enhancement of immunity. These approaches have yielded modest clinical activity in the past; however, the field is rapidly evolving with newer technology showing promising results. These new strategies utilize nanoparticle-targeted vaccines with codelivery of an antigen and adjuvant.
“This is a very exciting time in immunology, we're beginning to see real effects in patients, the real questions are yet to be asked, which fundamentally is whether we can prevent cancer,” said Dhodapkar. “That would fundamentally change cancer and would involve studying people without cancer, people who have mutated cells in their body and have a normal immune response against tumors.”
In addition to attempting to eradicate early cancer, other questions still remain regarding immuno-oncology, specifically mechanisms of response and resistance for the checkpoint inhibitors. Moreover, there is a need to find other dominant pathways in the immune system, like PD-1 and PD-L1, which could lead to highly effective combination strategies. As it stands now, a great deal of research is still required.