Using the patientâ€™s immune system to target and destroy cancer cells has long been a sought-after goal in oncology.
Using the patient’s immune system to target and destroy cancer cells has long been a sought-after goal in oncology, because such an approach would have considerable advantage over conventional therapies by sparing normal cells and by maintaining immune surveillance and memory to more effectively prevent cancer recurrences.1,2Many strategies that have shown promise in the preclinical setting, however, have frequently been disappointing in clinical trials, and the process of developing and applying the ideal cancer-specific immunotherapy in the clinic remains challenging.
“The idea of being able to vaccinate a patient against their cancer seems so tantalizingly simple, given the overwhelming success of preventative vaccines against infectious pathogens,” said Christopher A. Klebanoff, MD, assistant clinical investigator at the Center for Cancer Research of the National Cancer Institute and the National Institutes of Health in Washington, DC.
Jedd D. Wolchok, MD, PhD, on the Management of Side Effects Associated With Immunotherapies
Wolchok is a medical oncologist at Memorial Sloan Kettering Cancer Center.
“Unfortunately, high-quality clinical data supporting [the idea] that therapeutic cancer vaccines can be effective have been extremely limited, as the field is all too aware,” Klebanoff stated. He explained that there are many reasons why therapeutic cancer vaccines might fail.
“The tumor microenvironment can be highly immune-suppressive because of regulatory T cells and other immune-suppressive factors, such as expression of the co-inhibitory ligand (programmed death receptor ligand 1) PD-L1 on tumor cells and stroma. Additionally, the tumor-specific T-cell repertoire can be immunologically exhausted or even senescent. Finally, generating a sufficient number of tumor-reactive T cells to combat a rapidly growing tumor is not easy, particularly given the problems of immune suppression and immune exhaustion,” Klebanoff said.Klebanoff explained that “T cells can be radically potent,” mediating, in some cases, regression of every last cancer cell in some patients. He cautioned, however, that with such potency comes the possibility for toxicity.
“Unfortunately, the field has already experienced severe, and in some cases lethal, toxicities from immunotherapies targeting shared antigens between tumors and normal tissues, such as HER2/neu,” Klebanoff said. Because tumors frequently express an array of antigens that may not be specific to the tumor alone, the potential for autoimmunity exists, and therefore, collateral damage to normal tissues.1,2Autoimmunity may be induced by so-called adoptive immunotherapy approaches, whereby immune cells are stimulated and expanded in vitro and then reintroduced into the patient to provide immediate antitumor therapy.2Some of the adverse events (AEs) caused by this type of immunotherapy include colitis, liver and lung toxicity, and vitiligo.2
Autoimmunity may also be induced by the use of exogenously administered monoclonal antibodies, for example, those that are designed to remove critical inhibitory checkpoints of the immune system (eg; anticytotoxic T-lymphocyte antigen 4 [CTLA-4]). AEs that have been observed in this regard include arthritis, hypothyroidism, colitis, and vitiligo.2
Investigators have therefore sought to identify tumor-associated antigens (TAAs), such as MAGE-1, which is not expressed in most normal adult tissues and can be recognized by cytotoxic T-lymphocytes (CTLs) to use as vaccines.1
“As the adage goes, prevention is the best medicine. Ideally, this means choosing to target antigens which are uniquely expressed on cancers, but not normal tissues,” Klebanoff said. He explained that such targets could include unique epitopes generated from tumor-specific mutations, so-called cancer testis antigens that are only expressed on tumors, or viral-associated antigens such as those found in oncogenic viruses like human papillomavirus.
“As I and others in my group see it, this is one of the most pressing issues limiting the wide dissemination of T-cell immunotherapies to a broad range of cancers: finding suitable targets,” he said, noting how the use of new technologies has helped in this regard.
“The ability to quickly and cheaply sequence genomes means it is now possible to sequence a patient’s tumor and specifically look for tumor-specific antigens generated from mutations to target immunologically. Targeting tumor-specific mutations, ideally driver mutationsbut in practice any consistently expressed mutations would do—is perhaps the best way to ensure tumor-specificity without placing normal tissues at risk,” Klebanoff stated. He also noted the real possibility for highly selective T-cell therapies targeted at specific tumor markers to be more readily accessible in the future, such as cancer-testis antigen NY-ESO-1.  Vaccine-based therapies for cancer have often met with limited clinical success.1,3,4Klebanoff noted, however, that this could, in part, be attributed to the design of clinical trials. “For patients and oncologists alike, the only meaningful endpoint is whether a therapeutic approach, immunologic or otherwise, can demonstrably extend life. To accurately assess this, a trial must have an adequately sized, contemporaneous control arm to which the treatment is compared.” He suggested that the only successful trial using this measure is the sipuleucel-T trial in prostate cancer reported by Kantoff and coworkers in 2010, and he further noted that even the results of the trial have remained controversial.5,6
“Ultimately, the painful reality is that most vaccine-based immunotherapies have not performed well by these measures,” Klebanoff stated. “The reasons for failure [of vaccine-based therapies] are multifactorial, but as I see it, are mostly due to the fundamental problems of host immune-suppression, T-cell exhaustion, and a handicapped kinetics race between T cells and the tumor,” Klebanoff said.
Indeed, many factors, such as the nature of the patient population studied, work against the efficacy of cancer vaccines; patients in such trials often have end-stage disease with poor performance status, and may lack sufficient immune function (for example, owing to old age or the use of prior anticancer therapies) to mount an effective antitumor response.3Klebanoff also emphasized the differences in growth kinetics between the tumor and the attacking T cells, which must be overcome for a vaccine to be effective. Moreover, tumors have also evolved mechanisms to promote tolerance and evade immune detection, and the in vivo microenvironment around the tumor may significantly reduce the efficacy of such vaccines. For these reasons, combining vaccines with therapies to inhibit tumor-derived immuno-inhibitory signals may be one means of improving their efficacy.3
Despite the lack of improvement in efficacy for vaccine-based cancer therapies as described in a 2011 review,4the increasing knowledge about immunotherapies presents an opportunity for further improvement and refinement of strategy, according to Klebanoff. He also predicted a more widespread availability in the future of technologies such as chimeric antigen receptor (CAR) therapy, a treatment designed to make a patient’s own T cells more effectively target tumor cells.6
“I think a clear path forward is to game the system in our patient’s favor using adoptive T-cell immunotherapy. Each of the potential obstacles to successhost immune suppression, T-cell exhaustion, tumor growth versus T-cell growth kinetics—can be optimized with this approach. Prior host conditioning before cell infusion can disrupt the immune-suppressive environment, expansion of T cells ex vivo and selection of defined T-cell subsets can combat the issues related to T-cell exhaustion, and infusing up to 1 × 1011antitumor T cells clearly can tilt the kinetic race,” Klebanoff stated.