Update: Immunotherapy for melanoma

The concept of using the immune system to combat cancer in the body is centuries old, however it is only recently that continued research has led to significant advances in numerous immune-based drugs that can successfully be used in patients with advanced melanoma (stage III and IV). According to one expert, these recent advances in immunotherapy can offer melanoma patients an extended survival, giving much needed hope for this patient population.

In the past, chemotherapy agents and immune-based cytokine drugs such as interferon and interleukin were the mainstay treatment approaches used in patients with advanced melanoma. However, none of these agents could meaningfully improve the survival of this patient population.

“Immunotherapy has become a very fast-moving field and the strides we’ve made in drug development have led to an improved survival benefit in advanced stage melanoma patients,” said Debjani Sahni, M.D., director of the Cutaneous Oncology Program, Boston University School of Medicine, Boston.

Within our immune system, in addition to stimulatory receptors on T cells, there are also regulatory molecules called immune checkpoints. Their function is to prevent the immune system from going out of control and limit collateral damage, and therefore maintain immune homeostasis. Tumors, including melanoma can take advantage of this regulatory mechanism to avoid being eliminated by the immune system.

“Antibodies that inhibit these immune checkpoints, which normally act as nature’s brakes on the immune system, can release those brakes and unleash a much stronger immune effect on the tumor,” Dr. Sahni said.

BASIC PRINCIPAL

The principle of immunotherapy is based on enhancing the patient’s own immune system to recognize and destroy cancer cells more effectively. The greatest success in FDA-approved immunotherapy drugs has been checkpoint inhibitors such as CTLA-4 inhibitor (i.e. ipilimumab), and PD-1 inhibitors (i.e. pembrolizumab and nivolumab). More recently, talimogene laherparepvec (T-Vec), an oncolytic virus therapy that stimulates a more robust anti-tumor immune response has shown great promise.

All three checkpoint inhibitor drugs have shown a survival advantage when given in patients with advanced stage melanoma. Although they can have a durable effect on melanoma, it is only seen in a subset of patients. At present there are no good biologic predictors or biomarkers available to help clinicians identify those individuals who might benefit most from this type of therapy.

Compared to the anti-CTLA-4 inhibitor, the anti-PD-1 drugs are generally better tolerated and have greater survival benefit. According to Dr. Sahni, one way to improve the survival effect is to use anti-PD-1 inhibitors together with anti-CTLA-4 inhibitor as a combination therapy. Although the overall clinical efficacy of combination treatments can be greater, so is the side effect profile and as such, caution is advised when considering this treatment approach.

The oncolytic viral vaccine talimogene laherparepvec (T-VEC, ImlygicTM) is a genetically modified herpes simplex virus which has attenuated pathogenicity. The vaccine undergoes tumor selective replication and tumor lysis. In addition to having a local tumor-lytic effect, the genetic modification enables local production of GM-CSF (granulocyte-macrophage colony-stimulating-factor). This enables the recruitment and activation of antigen presenting cells and subsequently induces a tumor-specific systemic T-cell response. In addition to killing cancer cells where the viral vaccine is being injected, distant cancer cells have been shown to be impacted as well due to the induction of the systemic immune response. Dr. Sahni said that clinical trials are currently underway to combine this viral vaccine together with checkpoint inhibitors to improve clinical outcomes.

“There are many other checkpoint molecules as well as T cell stimulatory cell surface molecules that still need to be explored as potential immunotherapy drug development. Although we have taken giant steps towards improving survival in melanoma patients with regards to immunotherapy with impressive and often durable results, we still have further to go. At present the clinical benefit is limited to a subset of individuals and there is currently no good way to predict which patients are most likely to benefit from the drugs. Current research efforts are being directed to improve both these issues, and we are now entering into an exciting and dynamic field of personalized medicine,” Dr. Sahni said.

REFERENCES

S014, Updates on Immunotherapy in Melanoma, February 16th 2018, Debjani Sahni, MD