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Tumor Discovery Adjuvant immunotherapy in high-risk melanoma

of active autoimmune disease, use of corticosteroids or the unique and specific neoantigens of the individual
immunosuppressive therapy, having low-risk Stage IIIA patient. From the initial clinical studies of personalized
disease, and patient preferences. neoantigen-based vaccines, data supports a strong tumor-
specific immune response and anti-tumor activity against
4.2. Future direction of adjuvant immunotherapy cancer cells. 26-28
In the KN-054 and CM-238, RFS was noted to be around The mRNA-4157 is a new mRNA-based individualized
20–25%, 12–18 months after surgery. More studies are neoantigen therapy developed by Moderna, Inc. It consists
needed to improve the outcomes in this clinical domain, of a single-stranded mRNA, which can be coded for up
and there is an unmet need to further enhance the RFS in to 34 neoantigens. It is manufactured according to the
patients with resected melanoma. distinct mutational pattern of the patient’s tumor DNA

4.2.1. Adjuvant immunotherapy with dual agents sequence. These encoded neoantigen sequences are
translated once this vaccine is administered to the patient.
Interestingly, a recent randomized Phase III clinical trial to This leads to activations of the immune system and the
assess the combination of nivolumab plus ipilimumab as launch of an antitumor response by generating T-cells
adjuvant therapy in patients with resected high-risk node- specific to the tumor mutation sequence of that particular
positive disease did not show an improvement in relapse- patient’s cancer. 29
free survival over adjuvant nivolumab single-agent therapy
in resected Stage IIIB-D or IV melanoma. 18-20 KEYNOTE-942 (a phase II study of the efficacy
of adjuvant treatment with the personalized cancer
RELATIVITY-098 is another clinical trial that is vaccine mRNA-4157 and pembrolizumab in participants
currently underway to evaluate adjuvant immunotherapy with resected high-risk melanoma) has demonstrated
with nivolumab in combination with relatlimab (an anti- encouraging results. The study revealed significantly
LAG-3 antibody) compared to nivolumab alone after prolonged DMFS compared to pembrolizumab. In this
30
complete resection of stage III-IV melanoma, with pending trial, 157 high-risk stage cutaneous melanoma patients were
results. randomly assigned in a 2:1 ratio to receive either mRNA-
However, the PIVOT-12 trial, a Phase III randomized, 4157 combined with pembrolizumab or single-agent
open-label study comparing adjuvant immunotherapy pembrolizumab. The 18-month DMFS was statistically
with bempegaldesleukin combined with nivolumab versus significant for the combination therapy arm. Similarly, RFS
nivolumab alone after complete resection of melanoma in was 78.6% in the combination therapy group compared to
high-risk patients, has been canceled. This decision was 62.2% in the single-drug therapy group, respectively. At
based on disappointing results from the PIVOT IO-001 present, a Phase III randomized study has been initiated.
clinical trial, where the study endpoints of progression-free
survival and objective response rate were not met. 21 4.2.3. Role of neoadjuvant and adjuvant
immunotherapy therapy in resected Stage II melanoma
4.2.2. Personalized cancer vaccine The approach of neoadjuvant immunotherapy in patients
Another significant development in the last decade is the with resected Stage II melanoma is still evolving, with
use of vaccines for the treatment of cancer. encouraging preliminary results from Phase 2 clinical
trials, particularly with the combination of nivolumab and
Mutations taking place within the tumor cells can lead
to the development of unique epitopes of self-antigens, ipilimumab. The pathological responses were observed
in about 71% of cases, including a pathological complete
which are known as neoantigens or neoepitopes. With the response (pCR) or near pCR in 61% of cases. Furthermore,
22
advancements in next-generation sequencing technology,
these tumor-specific mutations in patients can be identified an improvement in quality of life, reduced rates of total
promptly and practically. It also helps to explore treatment lymph node dissection, and fewer surgical adverse events
31-33
options through early-phase clinical trials that target these were observed.
mutated proteins. Furthermore, these neoepitopes, which The use of pembrolizumab in the adjuvant clinical setting
have the potential to induce an immunogenic response, was evaluated in KEYNOTE-716, a placebo-controlled,
can be identified due to the development of technologies international, double-blind Phase III clinical trial. This
that predict major histocompatibility complex Class I study included patients with completely resected cutaneous
and II-presented epitopes. Overall, this has led to the melanoma of Stage IIB or IIC, randomized to receive
development of personalized cancer vaccinations for the either adjuvant pembrolizumab treatment or placebo for
treatment of tumors specific to an individual patient. 23-25 up to 12 months. It was noted that, for all the patients,
These vaccines ultimately trigger T-cell responses against at a median follow-up of 21 months, pembrolizumab

Volume 3 Issue 3 (2024) 7 doi: 10.36922/td.3143