A multicenter, open label non-randomized phase I/II dose escalation study with extension cohort to determine the safety, tolerability and immune modulating effects of the therapeutic LRPAP1 synthetic long peptide ( LRPAP7-30V-SLP) vaccine (TEIPP24) at different doses in HLA-A*0201-positive patients with non-small cell lung cancer (NSCLC).

Immunogenic tumors can be controlled by tumor-reactive T-cells either directly
or after checkpoint blockade. In the end, most tumors will develop mechanisms
to escape immune control. One of such a mechanism is formed by the functional
impairment of the intracellular peptide transporter TAP1/TAP2 by mutation of
downregulated expression. As a result the presentation of conventional T-cell
epitopes in HLA class I is lost, and hence tumor-reactive CD8+ T-cells fail to
recognize and kill tumor cells. This type of immune escape can occur in up to
50% of primary tumors and is increased in the metastatic lesions of such
tumors. The presence of these TAP defects correlate with worse
clinicopathological parameters and has been associated with loss of durable
benefit to checkpoint inhibition. The unmet need, therefore, is the development
of a therapy that can reinforce effective tumor-immunity to cancers displaying
TAP-defects for which conventional therapeutic cancer vaccines and/or
checkpoint blockade do not work. TEIPP therapy may fill this position by
reinstalling an effective antitumor response to TAP-defective tumors thereby
increasing the overall survival of patients failing first line therapy. While
TAP defects result in a failure to present the conventional tumor antigens in
HLA class I, a novel set of shared neoantigens - referred to as T-cell epitopes
associated with impaired peptide processing or *TEIPP* - becomes available for
recognition by CD8+ T-cells. We have identified a human TEIPP in the
ubiquitously expressed protein LRPAP1. This LRPAP1-TEIPP is able to activate
HLA-A*0201-restricted CD8+ T-cells that preferentially recognize a series of
TAP-negative/low tumor cells while remaining unresponsive to healthy cells of
the same tissue type. In addition, we identified the LRPAP7-30 synthetic long
peptide (LRPAP7-30V-SLP) sequence to stimulate HLA-A*0201-restricted
LRPAP21-30 -specific CD8+ T cells and showed that in vitro vaccination
resulted in a rapid expansion of T-cells able to specifically recognize
HLA-A*0201-positive, LRPAP1-positive and TAP-defective tumor cells.

Primary objectives
- A multicenter, open label non-randomized phase I/II dose escalation study
with extension cohort to determine the safety, tolerability and immunogenicity
of the therapeutic LRPAP1 synthetic long peptide ( LRPAP7-30V-SLP) vaccine
(TEIPP24) at different doses in HLA-A*0201-positive patients with non-small
cell lung cancer (NSCLC) failing first line therapy of checkpoint blockade
with/without chemotherapy and who can*t endure or are not willing to receive
2nd line treatment with docetaxel chemotherapy.

Secondary objectives
- To assess the specificity and immune modulatory effects of the vaccine.
- To assess the antigen and immune status of the patients.
- To determine progression free survival (PFS) and overall survival (OS) after
vaccination.
- To determine the radiological tumor response and tumor response duration
after vaccination according to RECIST v.1.1 criteria.

Study design: This is a prospective, single arm, multicenter, open-label, phase
I-II clinical study. HLA-A*0201-positive patients with NSCLC failing first
line of treatment will be enrolled in 3 cohorts and one extension cohort of 6
patients each to include 24 patients in total. The maximal total treatment
duration is 9 weeks. The first 6 patients will be enrolled in cohort 1, the
next 6 patients in cohort 2, the next 6 patients in cohort 3. In the extension
cohort, patients will receive the highest safe dose in combination with
pembrolizumab. The decision to start enrollment at the next dose level will be
made by assessing the safety after 3 out of 6 patients at the previous dose
level have completed vaccine therapy. The Principal Investigator (PI) will
study individual patient data related to baseline characteristics, safety, and
study medication administration for the patients necessary to assess per above
before decision to start enrollment at the next dose level. The PI will assess
information per above for relevant patients, summarize findings, and give a
recommendation whether or not he/she endorses the start of enrolment at the
next dose level. The summary and recommendation from the PI, including all
necessary individual patient background material, should be reviewed and
commented on by the DSMB members. After having received the opinion of the
DSMB, the PI can issue a written approval (or disapproval) regarding the start
of enrollment at the next dose level. No dose limiting toxicities are
anticipated based on previous clinical studies with synthetic long peptide
vaccines. Patients who have not received at least two vaccinations with TEIPP24
and for whom no pre-vaccination blood sample and two post-second vaccination
blood samples have been collected (all with sufficient peripheral blood
mononuclear cells (PBMCs)) are not evaluable for the HLA-A*0201-restricted
LRPAP21-30 -specific CD8+ T cells assays and will be replaced unless treatment
was stopped prematurely due to toxicity.

Patients will receive an off the shelf TEIPP24 vaccine mixed with Montanide
ISA-51 adjuvant, which will be admistered every three weeks for a period of
three rounds of vaccination. The TEIPP24 vaccine is dissolved in
dimethylsulfoxide, dilute with water for injection (WFI) and emulsified with
Montanide ISA-51 (Seppic). Patient cohort 1 will be treated with TEIPP24 at a
dose of 20ug of peptide, patients in cohort 2 with TEIPP24 at a dose of 40ug of
peptide and patients in cohort 3 with TEIPP24 at a dose of 100ug of peptide.
Patients will receive three rounds of vaccination three weeks apart via one
subcutaneous (SC) injection in a limb. Subsequently patients will be followed
until 1 year after the first vaccination. Patients in the extension cohort will
receive the highest safe dose in combination with pembrolizumab. Patients will
receive up to 3 cycles of pembrolizumab concurrently with the 3 TEIPP24
vaccinations (3 cycles every 3 weeks).

First line treatment of NSCLC (SCC & AC) consists of anti-PD-L1 checkpoint
inhibition (CPI) in combination with chemotherapy. Median progression free
survival ranges from 8-13 months (refs) after which no other treatment option
exists other than chemotherapy with docetaxel as 2nd line treatment. Docetaxel
is associated with treatment related adverse events, grade 3 or 4 in 55% of the
treated patients, whereas this is <15% in patients treated with PD-1 or PD-L1
CPI (refs) and not likely to be increased in combination with vaccination
(ref) . These adverse events caused by docetaxel mainly comprised neutropenia,
fatigue and nausea and especially life-threatening infections (refs). Due to
the side effects, most patients don*t want or can*t endure docetaxel, causing
a very low percentage of patients treated with second line treatment (below
25%) but when treated, an estimated 24% of SCC and 39% of AC NSCLC patients
survive 1 year only.

The TEIPP24 ( LRPAP7-30V-SLP) vaccine comprises an amino acid sequence derived
from LRPAP1, which is an ubiquitously expressed protein in human cells.
Therefore, the use of a peptide vaccine aiming to induce T-cell reactivity to
part of the LRPAP1 sequence carries two potential major risks: a)
cross-reactivity to proteins containing similar amino acid sequences, and b)
off-tumor/on-target reactivity, thus inflicting an immune response against
healthy tissues. Off tumor//on-target healthy tissue recognition has never been
observed in our extensive experience with the murine TEIPP model (ref).
Furthermore, the pre-clinical toxicity testing of human LRPAP1-specific CD8+
T-cell clones showed reactivity only against TAP-downregulated targets and
only to target cells that express LRPAP1. In addition, the targeted peptide
sequence has not been found in the healthy tissue database of HLA class
I-presented peptides (ref). Peptide vaccination has a very good safety profile
in general. Also SLP in Montanide ISA-51 vaccines are safe, based on our own
large series of trials (refs), specifically at the dose range of 20-100 *g per
peptide per injection with treatment emergent injection site reactions/systemic
allergic reactions NCI-CTC<2 (ref). Thus, based on the adata above, serious AEs
(SAEs) or suspected unexpected adverse reactions (SUSARs) related to the
vaccine are not expected. As with all vaccines, systemic allergic reaction may
occasionally occur, which can easily be treated with anti-histamine.

Patients will have adequate and appropriate checkups during this study to
monitor for potential (S)AEs and to minimize risk. The potential risks
identified from earlier peptide vaccination studies are judged to be
acceptable. Patients will undergo tumour biopsies as part of standard clinical
care. Furthermore, additional tumour biopsies will be obtained throughout the
course of the trial, only if an extra biopsy is safe and feasible. Peripheral
blood sampling will take place prior to each and after last vaccine
administration. The risk of blood withdrawals is negligible.